Am J Physiol Renal Physiol 308: F951–F955, 2015. First published February 25, 2015; doi:10.1152/ajprenal.00008.2015.
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Recent advances in renal hemodynamics: insights from bench experiments and computer simulations Anita T. Layton Department of Mathematics, Duke University, Durham, North Carolina Submitted 20 January 2015; accepted in final form 23 February 2015
Layton AT. Recent advances in renal hemodynamics: insights from bench experiments and computer simulations. Am J Physiol Renal Physiol 308: F951–F955, 2015. First published February 25, 2015; doi:10.1152/ajprenal.00008.2015.—It has been long known that the kidney plays an essential role in the control of body fluids and blood pressure and that impairment of renal function may lead to the development of diseases such as hypertension (Guyton AC, Coleman TG, Granger Annu Rev Physiol 34: 13– 46, 1972). In this review, we highlight recent advances in our understanding of renal hemodynamics, obtained from experimental and theoretical studies. Some of these studies were published in response to a recent Call for Papers of this journal: Renal Hemodynamics: Integrating with the Nephron and Beyond. renal hemodynamics; tubuloglomerular feedback; kidney disease
Renal Autoregulation THE GENERALLY STABLE GLOMERULAR filtration rate (GFR) is a result of renal autoregulation, as is the protection of glomerular capillaries from excessive intravascular pressure and shear stress. Renal autoregulation is mediated by several mechanisms (10, 27, 33). One such mechanism is the myogenic response, with which a rise in intravascular pressure elicits a local stretch-dependent constriction that generates a compensatory increase in vascular resistance (32). Another key autoregulatory mechanism is the tubuloglomerular feedback (TGF), which is a negative feedback response that balances glomerular filtration with tubular reabsorptive capacity (10, 27, 33). These renal autoregulatory mechanisms are believed to simultaneously insulate kidney function from variations in blood pressure and to protect glomerular capillaries from potential barotrauma. Indeed, impaired renal autoregulation (4, 61) and the resulting elevation in glomerular capillary pressure (28, 52) are thought to play an essential role in the pathogenesis of the progressive glomerular injury and sclerosis that has been observed in most chronic renal diseases, including diabetic nephropathy. The relative contributions of myogenic response and TGF in protecting glomerular capillaries from barotrauma remain controversial. A notable feature of the afferent arteriolar myogenic mechanism is that the response times for vasoconstriction and vasodilation differ significantly. Loutzenhiser and coworkers (44, 45) observed that the initial delay in the activation of pressure-dependent vasoconstriction was ⬃0.3 s, with the response profile approximated by an exponential having a time constant of 4 s. In contrast, vasodilation has a longer initial delay of ⬃1 s and a much slower response approximated by two exponentials having time constants of 1 and 14 s. A modeling study by Edwards and Layton (14) suggests that the
Address for reprint requests and other correspondence: A. Layton, Dept. of Mathematics, Duke Univ., Box 90320, Durham, NC 27708-0320 (e-mail: [email protected]). http://www.ajprenal.org
faster vasoconstriction can be attributed to the kinetic behavior of the voltage-activated L-type channels. If these observations are accurate, then the afferent arteriole would respond to high-frequency pressure fluctuations in blood pressure with a sustained vasoconstriction that is determined not by mean arteriolar pressure but by systolic pressure (44, 45). It is noteworthy that Just and Arendshorst (34) observed a stronger and faster dilator response than constrictor response, in direct contrast to the kinetics reported by Loutzenhiser and coworkers (44, 45). An explanation for this discrepancy has yet to be determined. TGF regulates distal tubular sodium load by adjusting the tone of the afferent arteriole and glomerular filtration rate in response to changes in NaCl concentration of the tubular fluid reaching the macula densa (5). TGF is regulated by a number of factors, including angiotensin (ANG) II (81), adenosine (75), adenosine triphosphate (ATP) (31, 65), atrial natriuretic factor (29), nitric oxide (NO) (42), and superoxide (O⫺ 2 ) (43). In addition, recent studies by Liu and coworkers (20, 87) suggest that aldosterone, via its effects on NO and O⫺ 2 , may play an important role in the control of TGF response. Aldo⫺ sterone increases O⫺ 2 production in the macula densa; O2 then scavenges NO and buffers the effect of NO on TGF activity. In an elegant study, Peti-Peterdi (62) demonstrated that TGF activation triggers a calcium wave, which spreads across the mesangial cell field and reaches the afferent arteriole. Intercellular communication pathways are an integral component of that calcium wave and of signal transmission in the juxtaglomerular apparatus (JGA), inasmuch as TGF calcium wave propagation can be prevented by gap junctional coupling inhibitors (62). Gap junctions comprise of connexin (Cx) subunits. In particular, the Cx protein Cx40, which is highly expressed in extraglomerular mesangial cells, has been proposed to be a facilitator of calcium signal transmission across the JGA (39, 76, 85). The role of Cx40 in TGF calcium wave is demonstrated by micropuncture experiments by Oppermann et al. (55) in Cx40-deficient mice, which indicate that deletion
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of Cx40 reduces TGF responsiveness by ⬃30%. Nonetheless, the fact that TGF response is not completely eliminated suggests either the involvement of a Cx other than Cx40 in TGF or an extracellular transmission pathway. How is renal autoregulation affected by changes in dietary salt? A key TGF signal is Cl⫺, the transport of which is mediated by Na-K-Cl cotransport (NKCC). A recent study by Schiessl et al. (70) indicates that a low-salt diet induces a shift from the isoform NKCC2-A to NKCC2-B primarily in the cortical thick ascending limb and macula densa cells. Given the markedly different ion affinities and reabsorptive capacities of its splice variants, the diet-induced shift in NKCC2 expression is believed to significantly impact NaCl reabsorption. To assess the validity of that hypothesis, Edwards et al. (13) used a theoretical approach: they developed a highly detailed computational model of the macula densa cell and thick ascending limb transport. Results of that modeling study suggest that the enhanced expression of NKCC2-B, which has a higher affinity for Cl⫺ than NKCC2-A, in the cortical thick ascending limb, where luminal Cl⫺ concentration is low especially with a low-salt diet, significantly enhances salt reabsorption in the thick limb and reduces salt delivery to the macula densa. Simulation results also predict that the NKCC2 isoform shift hyperpolarizes the macula densa basolateral cell membrane, which, taken in isolation, may inhibit the release of the TGF signal, thereby causing excessive early distal salt delivery and renal salt loss during a low-salt diet. That damaging effect may be prevented by an asymmetric TGF response that is more sensitive to flow increases (13). Both TGF and the myogenic response regulate glomerular filtration, in response to different signals, by affecting the afferent arteriolar tone. The individual contributions of these two mechanisms have been assessed by Sgouralis and Layton (71) using a detailed computational model of renal hemodynamics. The question is, given a perturbation in renal perfusion pressure, to what extent does each mechanism contribute to the stabilization of GFR? Their model simulations indicate a significant contribution of TGF to overall autoregulation only with a narrow band of perfusion pressure values (80 –110 mmHg). The two autoregulatory mechanisms leave their marks on nephron blood flow even in the absence of pressure perturbations, by generating sustained oscillations in arteriolar muscle tone, with a frequency of ⬃30 mHz for TGF and ⬃150 mHz for the myogenic response. A fascinating feature of these oscillations is that clusters of nearby nephrons, presumably with different characteristics and thus slightly different inherent frequencies, exhibit transient (not permanent) synchronization. Using laser speckle contrast imaging, Holstein-Rathlou et al. (26) found similar frequencies within small clusters of two or three nephrons, with larger clusters of nephrons with synchronized oscillations forming and dissolving. To better understand internephron interactions and synchronization, Marsh et al. (46) developed a computational model of 16 interacting nephrons. Their simulation results suggest that, despite the differing characteristics among the nephrons, some degree of synchrony persists, which triggers the formation of a selforganization system of nephrons. Nonetheless, owing to the asymmetry in the renal vascular network, that synchronization is not robust and can dissipate following a perturbation.
Renal Oxygenation The mechanisms underlying the development of renal hypoxia in many disease states have yet to be elucidated. That difficulty may be attributable, in part, to the fact that the kidney is a complex organ with unique three-dimensional organization of functional units. Anatomic studies in the medulla of rodent kidneys have revealed a highly structured organization of nephrons and vessels; that spatial organization is believed to play a key role in the oxygenation of the renal medulla (59). In the inner stripe of the outer medulla, descending vasa recta and some of the ascending vasa recta are isolated within tightly packed vascular bundles, separated from the thick ascending limbs and collecting ducts (3, 38). That arrangement continues into the upper inner medulla, where collecting ducts form clusters that exclude descending vasa recta (57, 58, 83). The structural organization of nephrons and vessels likely facilitates preferential interactions among neighboring structures and leads to radial gradients in solute concentrations. That is, for a given medullary cross section, interstitial solute concentrations may be different within versus outside the vascular bundles or collecting duct clusters. Now because the vascular bundles and collecting duct clusters are small, those concentration differences are likely small too and may even be negligible for solutes like NaCl, which reaches a high concentration within the renal medulla. However, for a solute with a much smaller baseline concentration, like O2, that “small” radial concentration gradient may still be substantial relative to baseline. Thus it may be argued that the structural organization of nephrons and vessels within the renal medulla may result in the sequestration of O2 within the vascular bundles (59). Despite receiving ⬃25% of the cardiac output, the mammalian kidney has low O2 levels, with tissue O2 tension of ⬃20 and 10 mmHg in the outer and inner medulla, respectively (51). Thus the kidney is susceptible to hypoxia. Its low O2 tension can be attributed in part to the high metabolic demands of the Na⫹-K⫹-ATPase, which drives salt reabsorption and accounts for a substantial fraction of the O2 consumption (QO2) in the medulla. In the outer medulla, the compartmentalization of medullary blood flow within the vascular bundle is believed to help preserve O2 supply to the inner medulla, but it also lowers the O2 tension in the interbundle regions. Because the thick limbs are found outside of the vascular bundles where O2 supply is low, they are particularly vulnerable to hypoxic injuries. Indeed, recent modeling studies have suggested that the thick ascending limb cells, particularly those of superficial nephrons, operate near hypoxia (8, 19). Also noteworthy are modeling studies of Edwards and coworkers (18, 84) that examine the distribution of medullary NO, taking into account the structural arrangements of the vascular bundles. Those studies demonstrate that differential NO concentrations may selectively alter medullary perfusion in different regions. Renal tissue hypoxia has been demonstrated during the acute phase of reperfusion after ischemia induced by blocking the aorta that supplies the kidney (40, 41, 72). However, these observations appear to be in disagreement with clinical studies that indicate relatively well-preserved oxygenation in the nonfunctional transplanted kidney (54, 63). Thus the question is: to what extent can acute kidney injury occur in the absence of wide-spread renal tissue hypoxia? To answer that question, Abdelkader et al. (1) measured renal O2 delivery, QO2, and
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cortical and inner medullary tissue PO2 during reperfusion after a period of ischemia localized to the kidney. They detected no significant reductions in tissue PO2 in the renal cortex or inner medulla, a result that may be explained by the simultaneous decreases in glomerular filtration and QO2. Nonetheless, pimonidazole adduct immunohistochemistry indicates localized tissue hypoxia in the outer medulla, which allows for the possibility of hypoxia contributing to acute kidney injury. Tissue PO2 is frequently assessed by data obtained using blood oxygen level-dependent (BOLD) MRI, an imaging technique where the concentration of deoxygenated hemoglobin molecules is reflected by tissue signal (53). BOLD MRI data are known to be influenced by various factors, including blood perfusion, hematocrit, intrinsic spin-spin relaxation rate, and oxygen permeability. To improve the extraction of tissue PO2 from renal BOLD data, Zhang et al. (86) developed a multistep data analysis method. First, Monte Carlo simulations are performed to estimate blood oxygen saturation (SHb) from BOLD signals. Then an oxygen transit model is used to convert SHb to tissue PO2. Their method was validated using a porcine model and appears promising for use in human subjects. The ratio of Na⫹ reabsorption (TNa) to QO2 represents a measure of the metabolic efficiency. TNa/QO2 is reduced in diabetes (56), hypertension (11), and chronic kidney disease (11). These observations have been interpreted as evidence for inefficiency utilization of oxygen for TNa in those pathophysiological states, due to shift in TNa to less efficient nephron segments or to mitochondrial dysfunction [as discussed in a recent review (7)]. However, it is important to note that QO2 Na has two components, one that depends on TNa, denoted QO , 2 basal and the other does not, denoted QO2 . With this notation, Na basal TNa/QO2 can be written as TNa/(QO ⫹ QO ). It can be seen 2 2 that a drop in metabolic efficiency for TNa is clearly reflected basal in the ratio TNa/QO2 only if QO is negligible compared with 2 active active QO2 ; otherwise, any changes in QO would have minimal 2 effect on QO2 and TNa/QO2. To estimate the fractional contribasal butions of QO to QO2, Evans et al. (16) performed a system2 atic review and conducted additional experiments in anesthetized rabbits. They estimated that under physiological condibasal tions, QO /QO2 varies hugely from 0 to 81.5%; that fraction 2 depends, in part, on fractional sodium excretion (FENa). Linear basal regression analysis predicted QO /QO2 of 12.7–16.5% when 2 FENa ⫽ 1%. Given these estimate, Evans et al. concluded that basal TNa/QO2 should be interpreted cautiously, because QO is by 2 no means negligible and may actually vary in ways that can be difficult to predict (16). As a result, it is conceivable that significant changes in TNa/QO2 may occur when TNa changes, even if metabolic efficiency remains unaltered. Renal Hemodynamics Under Pathophysiological Conditions There is much interest in better understanding the mechanisms by which renal autoregulation is impaired in diseases such as diabetes or hypertensive, and progress has been made. Myogenic response is known to be impaired under some pathophysiological conditions and disease models. One example is the Dahl salt-sensitive (SS) rats. These rats, when challenged with a high-salt diet, quickly develop glomerulosclerosis and proteinuria (67, 68). In a recent study, Ge et al. (22) report that the production of 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictor, is reduced in the
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renal vasculature of Dahl SS rats. In a related study (64), also performed on Dahl SS rat, Ren et al. indicate that a decrease in 20-HETE leads to the impairment of the constriction of the afferent arteriole and its autoregulatory response. Together, these findings suggest that endogenous formation of 20-HETE in the renal microcirculation may play a key role in modulating the autoregulatory response of the afferent arteriole. These studies further provide evidence that the susceptibility of SS rats to the development of hypertension-induced renal injury may be attributed, in part, to the deficiency in the renal production of 20-HETE. One implication of these results is that strategies that increase 20-HETE may restore the myogenic response (64). Renal autoregulation is impaired in diabetes, one of the leading causes of end-stage renal disease (15, 50, 82). The onset of diabetes is characterized by glomerular hyperfiltration (12). One open question concerns the roles of ANG II and adenosine receptors for controlling baseline renal blood flow or tubular Na⫹ transport in diabetes. Accordingly, Patinha et al. (60) studied the functions of these receptors in control and 2-wk streptozotocin-diabetic rats after intrarenal infusion of an ANG II AT1 receptor antagonist and an adenosine A1 receptor antagonist, separately or simultaneously. Their findings suggest that, via a unifying mechanism, ANG II and adenosine provide strict tonic control of renal blood flow and tubular Na⫹ transport; that result was obtained in both control and diabetic kidneys. Furthermore, glomerular hyperfiltration was observed as a consequence of increased vascular AT1 receptor activities, independently of any effect of adenosine A1 receptors. NO mediates vasodilation, increases renal blood flow, and inhibits renal QO2; taken together, NO can contribute to the increase of renal tissue oxygenation. Thus derangement of NO metabolism may be involved in the pathogenesis of diabetes and the progression to diabetic nephropathy (36, 37, 88). Hueper et al. (30) conducted the first study that determines the effect of systemic NO synthesis inhibition on systemic blood pressure and vascular conductance in a rat model of diabetic nephropathy. They used diffusion tensor imaging and BOLD imaging to conduct a noninvasive investigation of the intrarenal effects of NO metabolism. Following NO synthesis inhibition by nitro-L-arginine methyl ester (L-NAME) injection, they found a significant decrease in vascular conductance and increase of mean arteriolar pressure in control animals. In contrast, the systemic vascular reactivity upon L-NAME injection was significantly attenuated in diabetic rats, with minimal changes observed in mean arteriolar pressure and vascular conductance. As previously noted, TGF balances glomerular filtration with tubular reabsorptive capacity and elicits a reciprocal effect of distal NaCl delivery on single nephron glomerular filtration rate. This negative feedback is typically robust and remain intact under most circumstances. One exception to this rule is the subtotal nephrectomy (STN) rat model, where TGF responses were found to be highly variable and frequently paradoxical (73). It was suggested that this observation can be attributed to the need for the STN kidney to deal with a large excretory burden, per nephron. Under this circumstance, the kidney may opt to reduce the priority that is normally given to stabilizing nephron function (73). Singh and Thomson (74) tested that theory, with a focus on the effect of dietary salt, by conducting micropuncture studies. Their findings indicate that
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a high-salt diet leads to an anomalous TGF response in the STN kidney, which facilitates the delivery of both NaCl and fluid to the distal nephron. GRANTS This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-089066. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the author(s). AUTHOR CONTRIBUTIONS Author contributions: A.T.L. drafted manuscript; A.T.L. edited and revised manuscript; A.T.L. approved final version of manuscript. REFERENCES 1. Abdelkader A, Ho J, Ow CP, Eppel GA, Rajapakse NW, Schlaich MP, Evans RG. Renal oxygenation in acute renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 306: F1026 –F1038, 2014. 2. Aperia AC, Broberger CG, Söderlund S. Relationship between renal artery perfusion pressure and tubular sodium reabsorption. Am J Physiol 220: 1205–1212, 1971. 3. Bankir L, de Rouffignac C. Urinary concentrating ability: insights from comparative anatomy. Am J Physiol Regul Integr Comp Physiol 249: R643–R666, 1985. 4. Bidani AK, Schwartz MM, Lewis EF. Renal autoregulation and vulnerability to hypertensive injury in remnant kidney. Am J Physiol Renal Fluid Electrolyte Physiol 252: F1003–F1010, 1987. 5. Briggs JP, Schnermann J. Macula densa control of renin secretion and glomerular vascular tone: evidence for common cellular mechanisms. Renal Physiol 9: 193–203, 1986. 6. Cevese A, Guyton AC. Isohemic blood volume expansion in normal and areflexive dogs. Am J Physiol 231: 104 –111, 1976. 7. Che R, Yuan Y, Huang S, Zhang A. Mitochondrial dysfunction in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 306: F367–F378, 2014. 8. Chen J, Layton AT, Edwards A. A mathematical model of oxygen transport in the rat outer medulla: I. Model formulation and baseline results. Am J Physiol Renal Physiol 297: F517–F536, 2009. 9. Cowley AW Jr. Role of the renal medulla in volume and arterial pressure regulation. Am J Physiol Regul Integr Comp Physiol 273: R1–R15, 1997. 10. Cupples WA, Braam B. Assessment of renal autoregulation. Am J Physiol Renal Physiol 292: F1105–F1123, 2007. 11. Deng A, Tang T, Singh P, Wang C, Satriano J, Thomson SC, Blantz RC. Regulation of oxygen utilization by angiotensin II in chronic kidney disease. Kidney Int 75: 197–204, 2009. 12. Dengel DR, Goldberg AP, Mayuga RS, Kairis GM, Weir MR. Inslin resistance, elevated glomerular filtration fraction, and renal injury. Hypertension 28: 127–132, 1996. 13. Edwards A, Castrop H, Laghmani K, Vallon V, Layton AT. Regulation of NKCC2 isoform expression and NaCl transport in the thick ascending limb and macula densa cells. Am J Physiol Renal Physiol 307: F137–F146, 2014. 14. Edwards A, Layton AT. Calcium dynamics underlying the myogenic response of the renal afferent arteriole. Am J Physiol Renal Physiol 306: F34 –F48, 2014. 15. ERA-EDTA Registry. ERA-EDTA Registry Annual Report 2009. Amsterdam, The Netherlands: Academic Medical Center, Department of Medical Informatics, 2011. 16. Evans RG, Harrop GK, Ngo JP, Ow CP, O’Connor PM. Basal renal O2 consumption and the efficiency of O2 utilization for Na⫹ reabsorption. Am J Physiol Renal Physiol 306: F551–F561, 2014. 17. Franchini KG, Mattson DL, Cowley AW Jr. Vasopressin modulation of medullary blood flow and pressure-natriuresis-diuresis in the decerebrated rat. Am J Physiol Regul Integr Comp Physiol 272: R1472–R1479, 1997. 18. Fry BC, Edward A, Layton AT. Impacts of nitric oxide and superoxide on renal medullary oxygen transport and urine concentration. Am J Physiol Renal Physiol. First published January 28, 2015; 10.1152/ ajprenal.00600.2014.
19. Fry BC, Edward A, Sgouralis I, Layton AT. Impact of renal medullary three-dimensional architecture on oxygen transport. Am J Physiol Renal Physiol 307: F263–F272, 2014. 20. Fu Y, Hall JE, Lu D, Lin L, Manning RD Jr, Cheng L, GomezSanchez C, Juncos LA, Liu R. Aldosterone blunts tubuloglomerular feedback by activating macula densa mineralocorticoid receptors. Hypertension 59: 599 –606, 2012. 21. Garcia-Estañ J, Roman RJ. Role of renal interstitial hydrostatic pressure in the pressure diuresis response. Am J Physiol Renal Fluid Electrolyte Physiol 256: F63–F70, 1989. 22. Ge Y, Murphy SR, Fan F, Williams JM, Falck JR, Liu R, Roman RJ. Role of 20-HETE in the impaired myogenic and TGF responses of the Af-Art of Dahl salt-sensitive rats. Am J Physiol Renal Physiol 307: F509 –F515, 2014. 23. Granger JP. Pressure natriuresis. Role of renal interstitial hydrostatic pressure. Hypertension 19: I9 –17, 1992. 24. Granger JP, Alexander BT, Llinas M. Mechanisms of pressure natriuresis. Curr Hypertens Rep 4: 152–159, 2002. 25. Guyton AC, Coleman TG, Granger HJ. Circulation: Overall regulation. Annu Rev Physiol 34: 13–46, 1972. 26. Holstein-Rathlou NH, Sosnovtseva OV, Pavlov AN, Cupples WA, Sorensen CM, Marsh DJ. Nephron blood flow dynamics measured by laser speckle contrast imaging. Am J Physiol Renal Physiol 300: F319 – F329, 2011. 27. Holstein-Rathlou NH, Marsh DJ. Renal blood flow regulation and arterial pressure fluctuations: a case study in nonlinear dynamics. Physiol Rev 74: 637–681, 1994. 28. Hostetter TH, Rennke HG, Brenner BM. The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med 72: 375–380, 1982. 29. Huang CL, Cogan MG. Atrial natriuretic factor inhibits maximal tubuloglomerular feedback response. Am J Physiol Renal Fluid Electrolyte Physiol 252: F825–F828, 1987. 30. Hueper K, Hartung D, Gutberlet M, Gueler F, Sann H, Husen B, Wacker F, Reiche D. Assessment of impaired vascular reactivity in a rat model of diabetic nephropathy: effect of nitric oxide synthesis inhibition on intrarenal diffusion and oxygenation measured by magnetic resonance imaging. Am J Physiol Renal Physiol 305: F1428 –F1435, 2013. 31. Iwashima F, Yoshimoto T, Minami I, Sakurada M, Hirono Y, Hirata Y. Aldosterone induces superoxide generation via Rac1 activation in endothelial cells. Endocrinology 149: 1009 –1014, 2008. 32. Johnson PC. The myogenic response. In: Handbook of Physiology. The Cardiovascular System. Vascular Smooth Muscle. Bethesda, MD: Am. Physiol. Soc., 1981, sect. 2, vol. 2, p. 409 –442. 33. Just A. Mechanisms of renal blood flow autoregulation: dynamics and contributions. Am J Physiol Regul Integr Comp Physiol 292: R1–R17, 2007. 34. Just A, Arendhorst W. Nitric oxide blunts myogenic autoregulation in rat renal but not skeletal muscle circulation via tubuloglomerular feedback, J Physiol 569: 959 –974, 2005. 35. Kaloyanides GJ, DiBona GF, Raskin P. Pressure natriuresis in the isolated kidney. Am J Physiol 220: 1660 –1666, 1971. 36. Komers R, Anderson S. Glomerular endothelial NOS (eNOS) expression in type 2 diabetic patients with nephropathy. Nephrol Dial Transplant 23: 3037–3038, 2008. 37. Komers R, Anderson S. Paradoxes of nitric oxide in the diabetic kidney. Am J Physiol Renal Physiol 284: F1121–F1137, 2003. 38. Kriz W, Kaissling B. Structural organization of the mammalian kidney. In: The Kidney: Physiology and Pathophysiology (3 ed.). Philadelphia, PA: Lippincott Williams & Wilkins, 2000, p. 587–654. 39. Kurtz L, Madsen K, Kurt B, Jensen BL, Walter S, Banas B, Wagner C, Kurtz A. High-level connexin expression in the human juxtaglomerular apparatus. Nephron Physiol 116: p1–p8, 2010. 40. Legrand M, Almac E, Mik EG, Johannes T, Kandil A, Bezemer R, Payen D, Ince C. L-NIL prevents renal microvascular hypoxia and increase of renal oxygen consumption after ischemia-reperfusion in rats. Am J Physiol Renal Physiol 296: F1109 –F1117, 2009. 41. Legrand M, Kandil A, Payen D, Ince C. Effects of sepiapterin infusion on renal oxygenation and early acute renal injury after suprarenal aortic clamping in rats. J Cardiovasc Pharmacol 58: 192–198, 2011. 42. Liu R, Pittner J, Persson AE. Changes of cell volume and nitric oxide concentration in macula densa cells caused by changes in luminal NaCl concentration. J Am Soc Nephrol 13: 2688 –2696, 2002.
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Review RENAL HEMODYNAMICS 43. Liu R, Ren Y, Garvin JL, Carretero OA. Superoxide enhances tubuloglomerular feed-back by constricting the afferent arteriole. Kidney Int 66: 268 –274, 2004. 44. Loutzenhiser R, Bidani A, Chilton L. Renal myogenic response: kinetic attributes and physiologic role. Circ Res 90: 1316 –1324, 2002. 45. Loutzenhiser R, Bidani A, Wang X. Systolic pressure and the myogenic response of the renal afferent arteriole. Acta Physiol Scand 181: 404 –413, 2004. 46. Marsh DJ, Wexler AS, Brazhe A, Postnov DE, Sosnovtseva OV, Holstein-Rathlou NH. Multinephron dynamics on the renal vascular network. Am J Physiol Renal Physiol 304: F88 –F102, 2013. 47. Martino JA, Earley LE. Relationship between intrarenal hydrostatic pressure and hemodynamically induced changes in sodium excretion. Circ Res 23: 371–386, 1968. 48. Moss R, Layton AT. Dominant factors that govern pressure natriuresis in diuresis and antidiuresis: a mathematical model. Am J Physiol Renal Physiol 306: F952–F969, 2014. 49. Moss R, Thomas SR. Hormonal regulation of salt and water excretion: a mathematical model of whole kidney function and pressure natriuresis. Am J Physiol Renal Physiol 306: F224 –F248, 2014. 50. National Institute of Diabetes and Digestive and Kidney Diseases. U. S. Renal Data System, USRDS 2009 Annual Data Report. Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, 2009. 51. Neuhofer W, Beck FX. Cell survival in the hostile environment of the renal medulla. Annu Rev Physiol 67: 531–555, 2005. 52. Neuringer JR, Brenner BM. Hemodynamic theory of progressive renal disease: a 10-year update in brief review. Am J Kidney Dis 22: 98 –104, 1993. 53. Ogawa S, Lee TM, Kay AR, Tank DW. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci USA 87: 9868 –9872, 1990. 54. Oostendorp M, de Vries EE, Slenter JM, Peutz-Kootstra CJ, Snoeijs MG, Post MJ, van Heurn LW, Backes WH. MRI of renal oxygenation and function after normothermic ischemia-reperfusion injury. NMR Biomed 24: 194 –200, 2011. 55. Oppermann M, Carota I, Schiessl I, Eisner C, Castrop H, Schnermann J. Direct assessment of tubuloglomerular feedback responsiveness in connexin 40-deficient mice. Am J Physiol Renal Physiol 304: F1181– F1186, 2013. 56. Palm F, Fasching A, Hansell P, Kallskog O. Nitric oxide originating from NOS1 controls oxygen utilization and electrolyte transport efficiency in the diabetic kidney. Am J Physiol Renal Physiol 298: F416 –F420, 2010. 57. Pannabecker TL, Dantzler WH. Three-dimensional lateral and vertical relationship of inner medullary loops of Henle and collecting duct. Am J Physiol Renal Physiol 287: F767–F774, 2004. 58. Pannabecker TL, Dantzler WH. Three-dimensional architecture of inner medullary vasa recta. Am J Physiol Renal Physiol 290: F1355–F1366, 2006. 59. Pannabecker TL, Layton AT. Targeted delivery of solutes and oxygen in the renal medulla: role of microvessel architecture. Am J Physiol Renal Physiol 307: F649 –F655, 2014. 60. Patinha D, Fasching A, Pinho D, Albino-Teixeira A, Morato M, Palm F. Angiotensin II contributes to glomerular hyperfiltration in diabetic rats independently of adenosine type I receptors. Am J Physiol Renal Physiol 304: F614 –F622, 2013. 61. Pelayo JC, Westcott JY. Impaired autoregulation of glomerular capillary hydrostatic pressure in the rat remnant kidney nephron. J Clin Invest 88: 101–105, 1991. 62. Peti-Peterdi J. Calcium wave of tubuloglomerular feedback. Am J Physiol Renal Physiol 291: F473–F480, 2006. 63. Oostendorp M, de Vries EE, Slenter JM, Peutz-Kootstra CJ, Snoeijs MG, Post MJ, van Heurn LW, Backes WH. MRI of renal oxygenation and function after normothermic ischemia-reperfusion injury. NMR Biomed 24: 194 –200, 2011. 64. Ren Y, D’Ambrosio MA, Garvin JL, Peterson EL, Carretero OA. Mechanism of impaired afferent arteriole myogenic response in Dahl salt-sensitive rats: role of 20-HETE. Am J Physiol Renal Physiol 307: F533–F538, 2014. 65. Ren Y, Garvin JL, Liu R, Carretero OA. Role of macula densa adenosine triphosphate (ATP) in tubuloglomerular feedback. Kidney Int 66: 1479 –1485, 2004.
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66. Roman RJ, Cowley AW Jr, Garcia-Estañ J, Lombard JH. Pressurediuresis in volume-expanded rats. Cortical and medullary hemodynamics. Hypertension 12: 168 –176, 1988. 67. Roman RJ, Alonso-Galicia M, Wilson TW. Renal P450 metabolites of arachidonic acid and the development of hypertension in Dahl saltsensitive rats. Am J Hypertens 10: 63S–67S, 1997. 68. Roman RJ, Ma YH, Frohlich B, Markham B. Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. Hypertension 21: 985–988, 1993. 69. Romero JC, Knox FG. Mechanisms underlying pressure-related natriuresis: the role of the renin-angiotensin and prostaglandin systems. State of the art lecture. Hypertension 11: 724 –738, 1988. 70. Schiessl IM, Rosenauer A, Kattler V, Minuth WW, Oppermann M, Castrop H. Dietary salt intake modulates differential splicing of the Na-K-2Cl cotransporter NKCC2. Am J Physiol Renal Physiol 305: F1139 –F1148, 2013. 71. Sgouralis I, Layton AT. Theoretical assessment of renal autoregulatory mechanisms. Am J Physiol Renal Physiol 306: F1357–F1371, 2014. 72. Siegemund M, van Bommel J, Stegenga ME, Studer W, van Iterson M, Annaheim S, Mebazaa A, Ince C. Aortic cross-clamping and reperfusion in pigs reduces microvascular oxygenation by altered systemic and regional blood flow distribution. Anesth Analg 111: 345–353, 2010. 73. Singh P, Deng A, Blantz RC, Thomson SC. Unexpected effect of angiotensin AT1 blockade on tubuloglomerular feedback in early subtotal nephrectomy. Am J Physiol Renal Physiol 296: F1158 –F1165, 2009. 74. Singh P, Thomson SC. Salt sensitivity of tubuloglomerular feedback in the early remnant kidney. Am J Physiol Renal Physiol 306: F172–F180, 2014. 75. Sun D, Samuelson LC, Yang T, Huang Y, Paliege A, Saunders T, Briggs J, Schnermann J. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc Natl Acad Sci USA 98: 9983–9988, 2001. 76. Takenaka T, Inoue T, Kanno Y, Okada H, Meaney KR, Hill CE, Suzuki H. Expression and role of connexins in the rat renal vasculature. Kidney Int 73: 415–422, 2008. 77. Vallon V, Osswald H, Blantz RC, Thomson S. Potential role of luminal potassium in tubuglomerular feedback. J Am Soc Nephrol 8: 1831–1837, 1997. 78. Vallon V, Thomson SC. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu Rev Physiol 74: 351–375, 2012. 79. Weinstein AM. A mathematical model of rat ascending Henle limb. III. Tubular function. Am J Physiol Renal Physiol 298: F543–F556, 2010. 80. Weinstein AM, Krahn TA. A mathematical model of rat ascending Henle limb. II. Epithelial function. Am J Physiol Renal Physiol 298: F525–F542, 2010. 81. Welch WJ, Wilcox CS. Feedback responses during sequential inhibition of angiotensin and thromboxane. Am J Physiol Renal Fluid Electrolyte Physiol 258: F457–F466, 1990. 82. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27: 1047–1053, 2004. 83. Yuan J, Pannabecker TL. Architecture of inner medullary descending and ascending vasa recta: pathways for countercurrent exchange. Am J Physiol Renal Physiol 299: F265–F272, 2010. 84. Zhang W, Edwards A. A model of nitric oxide tubulovascular cross talk in a renal outer medullary cross section. Am J Physiol Renal Physiol 292: F711–F722, 2007. 85. Zhang J, Hill CE. Differential connexin expression in preglomerular and postglomerular vasculature: accentuation during diabetes. Kidney Int 68: 1171–1185, 2005. 86. Zhang JL, Morrell G, Rusinek H, Warner L, Vivier PH, Cheung AK, Lerman LO, Lee VS. Measurement of renal tissue oxygenation with blood oxygen level-dependent MRI and oxygen transit modeling. Am J Physiol Renal Physiol 306: F579 –F587, 2014. 87. Zhang Q, Lin L, Lu Y, Liu H, Duan Y, Zhu X, Zou C, Manning RD Jr, Liu R. Interaction between nitric oxide and superoxide in the macula densa in aldosterone-induced alterations of tubuloglomerular feedback. Am J Physiol Renal Physiol 304: F326 –F332, 2013. 88. Zhao HJ, Wang Cheng H S, Chang MZ, Takahashi T, Fogo AB, Breyer MD, Harris RC. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol 17: 2664 –2669, 2006.
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Recent advances in renal hemodynamics: insights from bench experiments and computer simulations Anita T. Layton Department of Mathematics, Duke University, Durham, North Carolina Submitted 20 January 2015; accepted in final form 23 February 2015
Layton AT. Recent advances in renal hemodynamics: insights from bench experiments and computer simulations. Am J Physiol Renal Physiol 308: F951–F955, 2015. First published February 25, 2015; doi:10.1152/ajprenal.00008.2015.—It has been long known that the kidney plays an essential role in the control of body fluids and blood pressure and that impairment of renal function may lead to the development of diseases such as hypertension (Guyton AC, Coleman TG, Granger Annu Rev Physiol 34: 13– 46, 1972). In this review, we highlight recent advances in our understanding of renal hemodynamics, obtained from experimental and theoretical studies. Some of these studies were published in response to a recent Call for Papers of this journal: Renal Hemodynamics: Integrating with the Nephron and Beyond. renal hemodynamics; tubuloglomerular feedback; kidney disease
Renal Autoregulation THE GENERALLY STABLE GLOMERULAR filtration rate (GFR) is a result of renal autoregulation, as is the protection of glomerular capillaries from excessive intravascular pressure and shear stress. Renal autoregulation is mediated by several mechanisms (10, 27, 33). One such mechanism is the myogenic response, with which a rise in intravascular pressure elicits a local stretch-dependent constriction that generates a compensatory increase in vascular resistance (32). Another key autoregulatory mechanism is the tubuloglomerular feedback (TGF), which is a negative feedback response that balances glomerular filtration with tubular reabsorptive capacity (10, 27, 33). These renal autoregulatory mechanisms are believed to simultaneously insulate kidney function from variations in blood pressure and to protect glomerular capillaries from potential barotrauma. Indeed, impaired renal autoregulation (4, 61) and the resulting elevation in glomerular capillary pressure (28, 52) are thought to play an essential role in the pathogenesis of the progressive glomerular injury and sclerosis that has been observed in most chronic renal diseases, including diabetic nephropathy. The relative contributions of myogenic response and TGF in protecting glomerular capillaries from barotrauma remain controversial. A notable feature of the afferent arteriolar myogenic mechanism is that the response times for vasoconstriction and vasodilation differ significantly. Loutzenhiser and coworkers (44, 45) observed that the initial delay in the activation of pressure-dependent vasoconstriction was ⬃0.3 s, with the response profile approximated by an exponential having a time constant of 4 s. In contrast, vasodilation has a longer initial delay of ⬃1 s and a much slower response approximated by two exponentials having time constants of 1 and 14 s. A modeling study by Edwards and Layton (14) suggests that the
Address for reprint requests and other correspondence: A. Layton, Dept. of Mathematics, Duke Univ., Box 90320, Durham, NC 27708-0320 (e-mail: [email protected]). http://www.ajprenal.org
faster vasoconstriction can be attributed to the kinetic behavior of the voltage-activated L-type channels. If these observations are accurate, then the afferent arteriole would respond to high-frequency pressure fluctuations in blood pressure with a sustained vasoconstriction that is determined not by mean arteriolar pressure but by systolic pressure (44, 45). It is noteworthy that Just and Arendshorst (34) observed a stronger and faster dilator response than constrictor response, in direct contrast to the kinetics reported by Loutzenhiser and coworkers (44, 45). An explanation for this discrepancy has yet to be determined. TGF regulates distal tubular sodium load by adjusting the tone of the afferent arteriole and glomerular filtration rate in response to changes in NaCl concentration of the tubular fluid reaching the macula densa (5). TGF is regulated by a number of factors, including angiotensin (ANG) II (81), adenosine (75), adenosine triphosphate (ATP) (31, 65), atrial natriuretic factor (29), nitric oxide (NO) (42), and superoxide (O⫺ 2 ) (43). In addition, recent studies by Liu and coworkers (20, 87) suggest that aldosterone, via its effects on NO and O⫺ 2 , may play an important role in the control of TGF response. Aldo⫺ sterone increases O⫺ 2 production in the macula densa; O2 then scavenges NO and buffers the effect of NO on TGF activity. In an elegant study, Peti-Peterdi (62) demonstrated that TGF activation triggers a calcium wave, which spreads across the mesangial cell field and reaches the afferent arteriole. Intercellular communication pathways are an integral component of that calcium wave and of signal transmission in the juxtaglomerular apparatus (JGA), inasmuch as TGF calcium wave propagation can be prevented by gap junctional coupling inhibitors (62). Gap junctions comprise of connexin (Cx) subunits. In particular, the Cx protein Cx40, which is highly expressed in extraglomerular mesangial cells, has been proposed to be a facilitator of calcium signal transmission across the JGA (39, 76, 85). The role of Cx40 in TGF calcium wave is demonstrated by micropuncture experiments by Oppermann et al. (55) in Cx40-deficient mice, which indicate that deletion
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of Cx40 reduces TGF responsiveness by ⬃30%. Nonetheless, the fact that TGF response is not completely eliminated suggests either the involvement of a Cx other than Cx40 in TGF or an extracellular transmission pathway. How is renal autoregulation affected by changes in dietary salt? A key TGF signal is Cl⫺, the transport of which is mediated by Na-K-Cl cotransport (NKCC). A recent study by Schiessl et al. (70) indicates that a low-salt diet induces a shift from the isoform NKCC2-A to NKCC2-B primarily in the cortical thick ascending limb and macula densa cells. Given the markedly different ion affinities and reabsorptive capacities of its splice variants, the diet-induced shift in NKCC2 expression is believed to significantly impact NaCl reabsorption. To assess the validity of that hypothesis, Edwards et al. (13) used a theoretical approach: they developed a highly detailed computational model of the macula densa cell and thick ascending limb transport. Results of that modeling study suggest that the enhanced expression of NKCC2-B, which has a higher affinity for Cl⫺ than NKCC2-A, in the cortical thick ascending limb, where luminal Cl⫺ concentration is low especially with a low-salt diet, significantly enhances salt reabsorption in the thick limb and reduces salt delivery to the macula densa. Simulation results also predict that the NKCC2 isoform shift hyperpolarizes the macula densa basolateral cell membrane, which, taken in isolation, may inhibit the release of the TGF signal, thereby causing excessive early distal salt delivery and renal salt loss during a low-salt diet. That damaging effect may be prevented by an asymmetric TGF response that is more sensitive to flow increases (13). Both TGF and the myogenic response regulate glomerular filtration, in response to different signals, by affecting the afferent arteriolar tone. The individual contributions of these two mechanisms have been assessed by Sgouralis and Layton (71) using a detailed computational model of renal hemodynamics. The question is, given a perturbation in renal perfusion pressure, to what extent does each mechanism contribute to the stabilization of GFR? Their model simulations indicate a significant contribution of TGF to overall autoregulation only with a narrow band of perfusion pressure values (80 –110 mmHg). The two autoregulatory mechanisms leave their marks on nephron blood flow even in the absence of pressure perturbations, by generating sustained oscillations in arteriolar muscle tone, with a frequency of ⬃30 mHz for TGF and ⬃150 mHz for the myogenic response. A fascinating feature of these oscillations is that clusters of nearby nephrons, presumably with different characteristics and thus slightly different inherent frequencies, exhibit transient (not permanent) synchronization. Using laser speckle contrast imaging, Holstein-Rathlou et al. (26) found similar frequencies within small clusters of two or three nephrons, with larger clusters of nephrons with synchronized oscillations forming and dissolving. To better understand internephron interactions and synchronization, Marsh et al. (46) developed a computational model of 16 interacting nephrons. Their simulation results suggest that, despite the differing characteristics among the nephrons, some degree of synchrony persists, which triggers the formation of a selforganization system of nephrons. Nonetheless, owing to the asymmetry in the renal vascular network, that synchronization is not robust and can dissipate following a perturbation.
Renal Oxygenation The mechanisms underlying the development of renal hypoxia in many disease states have yet to be elucidated. That difficulty may be attributable, in part, to the fact that the kidney is a complex organ with unique three-dimensional organization of functional units. Anatomic studies in the medulla of rodent kidneys have revealed a highly structured organization of nephrons and vessels; that spatial organization is believed to play a key role in the oxygenation of the renal medulla (59). In the inner stripe of the outer medulla, descending vasa recta and some of the ascending vasa recta are isolated within tightly packed vascular bundles, separated from the thick ascending limbs and collecting ducts (3, 38). That arrangement continues into the upper inner medulla, where collecting ducts form clusters that exclude descending vasa recta (57, 58, 83). The structural organization of nephrons and vessels likely facilitates preferential interactions among neighboring structures and leads to radial gradients in solute concentrations. That is, for a given medullary cross section, interstitial solute concentrations may be different within versus outside the vascular bundles or collecting duct clusters. Now because the vascular bundles and collecting duct clusters are small, those concentration differences are likely small too and may even be negligible for solutes like NaCl, which reaches a high concentration within the renal medulla. However, for a solute with a much smaller baseline concentration, like O2, that “small” radial concentration gradient may still be substantial relative to baseline. Thus it may be argued that the structural organization of nephrons and vessels within the renal medulla may result in the sequestration of O2 within the vascular bundles (59). Despite receiving ⬃25% of the cardiac output, the mammalian kidney has low O2 levels, with tissue O2 tension of ⬃20 and 10 mmHg in the outer and inner medulla, respectively (51). Thus the kidney is susceptible to hypoxia. Its low O2 tension can be attributed in part to the high metabolic demands of the Na⫹-K⫹-ATPase, which drives salt reabsorption and accounts for a substantial fraction of the O2 consumption (QO2) in the medulla. In the outer medulla, the compartmentalization of medullary blood flow within the vascular bundle is believed to help preserve O2 supply to the inner medulla, but it also lowers the O2 tension in the interbundle regions. Because the thick limbs are found outside of the vascular bundles where O2 supply is low, they are particularly vulnerable to hypoxic injuries. Indeed, recent modeling studies have suggested that the thick ascending limb cells, particularly those of superficial nephrons, operate near hypoxia (8, 19). Also noteworthy are modeling studies of Edwards and coworkers (18, 84) that examine the distribution of medullary NO, taking into account the structural arrangements of the vascular bundles. Those studies demonstrate that differential NO concentrations may selectively alter medullary perfusion in different regions. Renal tissue hypoxia has been demonstrated during the acute phase of reperfusion after ischemia induced by blocking the aorta that supplies the kidney (40, 41, 72). However, these observations appear to be in disagreement with clinical studies that indicate relatively well-preserved oxygenation in the nonfunctional transplanted kidney (54, 63). Thus the question is: to what extent can acute kidney injury occur in the absence of wide-spread renal tissue hypoxia? To answer that question, Abdelkader et al. (1) measured renal O2 delivery, QO2, and
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cortical and inner medullary tissue PO2 during reperfusion after a period of ischemia localized to the kidney. They detected no significant reductions in tissue PO2 in the renal cortex or inner medulla, a result that may be explained by the simultaneous decreases in glomerular filtration and QO2. Nonetheless, pimonidazole adduct immunohistochemistry indicates localized tissue hypoxia in the outer medulla, which allows for the possibility of hypoxia contributing to acute kidney injury. Tissue PO2 is frequently assessed by data obtained using blood oxygen level-dependent (BOLD) MRI, an imaging technique where the concentration of deoxygenated hemoglobin molecules is reflected by tissue signal (53). BOLD MRI data are known to be influenced by various factors, including blood perfusion, hematocrit, intrinsic spin-spin relaxation rate, and oxygen permeability. To improve the extraction of tissue PO2 from renal BOLD data, Zhang et al. (86) developed a multistep data analysis method. First, Monte Carlo simulations are performed to estimate blood oxygen saturation (SHb) from BOLD signals. Then an oxygen transit model is used to convert SHb to tissue PO2. Their method was validated using a porcine model and appears promising for use in human subjects. The ratio of Na⫹ reabsorption (TNa) to QO2 represents a measure of the metabolic efficiency. TNa/QO2 is reduced in diabetes (56), hypertension (11), and chronic kidney disease (11). These observations have been interpreted as evidence for inefficiency utilization of oxygen for TNa in those pathophysiological states, due to shift in TNa to less efficient nephron segments or to mitochondrial dysfunction [as discussed in a recent review (7)]. However, it is important to note that QO2 Na has two components, one that depends on TNa, denoted QO , 2 basal and the other does not, denoted QO2 . With this notation, Na basal TNa/QO2 can be written as TNa/(QO ⫹ QO ). It can be seen 2 2 that a drop in metabolic efficiency for TNa is clearly reflected basal in the ratio TNa/QO2 only if QO is negligible compared with 2 active active QO2 ; otherwise, any changes in QO would have minimal 2 effect on QO2 and TNa/QO2. To estimate the fractional contribasal butions of QO to QO2, Evans et al. (16) performed a system2 atic review and conducted additional experiments in anesthetized rabbits. They estimated that under physiological condibasal tions, QO /QO2 varies hugely from 0 to 81.5%; that fraction 2 depends, in part, on fractional sodium excretion (FENa). Linear basal regression analysis predicted QO /QO2 of 12.7–16.5% when 2 FENa ⫽ 1%. Given these estimate, Evans et al. concluded that basal TNa/QO2 should be interpreted cautiously, because QO is by 2 no means negligible and may actually vary in ways that can be difficult to predict (16). As a result, it is conceivable that significant changes in TNa/QO2 may occur when TNa changes, even if metabolic efficiency remains unaltered. Renal Hemodynamics Under Pathophysiological Conditions There is much interest in better understanding the mechanisms by which renal autoregulation is impaired in diseases such as diabetes or hypertensive, and progress has been made. Myogenic response is known to be impaired under some pathophysiological conditions and disease models. One example is the Dahl salt-sensitive (SS) rats. These rats, when challenged with a high-salt diet, quickly develop glomerulosclerosis and proteinuria (67, 68). In a recent study, Ge et al. (22) report that the production of 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictor, is reduced in the
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renal vasculature of Dahl SS rats. In a related study (64), also performed on Dahl SS rat, Ren et al. indicate that a decrease in 20-HETE leads to the impairment of the constriction of the afferent arteriole and its autoregulatory response. Together, these findings suggest that endogenous formation of 20-HETE in the renal microcirculation may play a key role in modulating the autoregulatory response of the afferent arteriole. These studies further provide evidence that the susceptibility of SS rats to the development of hypertension-induced renal injury may be attributed, in part, to the deficiency in the renal production of 20-HETE. One implication of these results is that strategies that increase 20-HETE may restore the myogenic response (64). Renal autoregulation is impaired in diabetes, one of the leading causes of end-stage renal disease (15, 50, 82). The onset of diabetes is characterized by glomerular hyperfiltration (12). One open question concerns the roles of ANG II and adenosine receptors for controlling baseline renal blood flow or tubular Na⫹ transport in diabetes. Accordingly, Patinha et al. (60) studied the functions of these receptors in control and 2-wk streptozotocin-diabetic rats after intrarenal infusion of an ANG II AT1 receptor antagonist and an adenosine A1 receptor antagonist, separately or simultaneously. Their findings suggest that, via a unifying mechanism, ANG II and adenosine provide strict tonic control of renal blood flow and tubular Na⫹ transport; that result was obtained in both control and diabetic kidneys. Furthermore, glomerular hyperfiltration was observed as a consequence of increased vascular AT1 receptor activities, independently of any effect of adenosine A1 receptors. NO mediates vasodilation, increases renal blood flow, and inhibits renal QO2; taken together, NO can contribute to the increase of renal tissue oxygenation. Thus derangement of NO metabolism may be involved in the pathogenesis of diabetes and the progression to diabetic nephropathy (36, 37, 88). Hueper et al. (30) conducted the first study that determines the effect of systemic NO synthesis inhibition on systemic blood pressure and vascular conductance in a rat model of diabetic nephropathy. They used diffusion tensor imaging and BOLD imaging to conduct a noninvasive investigation of the intrarenal effects of NO metabolism. Following NO synthesis inhibition by nitro-L-arginine methyl ester (L-NAME) injection, they found a significant decrease in vascular conductance and increase of mean arteriolar pressure in control animals. In contrast, the systemic vascular reactivity upon L-NAME injection was significantly attenuated in diabetic rats, with minimal changes observed in mean arteriolar pressure and vascular conductance. As previously noted, TGF balances glomerular filtration with tubular reabsorptive capacity and elicits a reciprocal effect of distal NaCl delivery on single nephron glomerular filtration rate. This negative feedback is typically robust and remain intact under most circumstances. One exception to this rule is the subtotal nephrectomy (STN) rat model, where TGF responses were found to be highly variable and frequently paradoxical (73). It was suggested that this observation can be attributed to the need for the STN kidney to deal with a large excretory burden, per nephron. Under this circumstance, the kidney may opt to reduce the priority that is normally given to stabilizing nephron function (73). Singh and Thomson (74) tested that theory, with a focus on the effect of dietary salt, by conducting micropuncture studies. Their findings indicate that
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a high-salt diet leads to an anomalous TGF response in the STN kidney, which facilitates the delivery of both NaCl and fluid to the distal nephron. GRANTS This work was supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-089066. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the author(s). AUTHOR CONTRIBUTIONS Author contributions: A.T.L. drafted manuscript; A.T.L. edited and revised manuscript; A.T.L. approved final version of manuscript. REFERENCES 1. Abdelkader A, Ho J, Ow CP, Eppel GA, Rajapakse NW, Schlaich MP, Evans RG. Renal oxygenation in acute renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 306: F1026 –F1038, 2014. 2. Aperia AC, Broberger CG, Söderlund S. Relationship between renal artery perfusion pressure and tubular sodium reabsorption. Am J Physiol 220: 1205–1212, 1971. 3. Bankir L, de Rouffignac C. Urinary concentrating ability: insights from comparative anatomy. Am J Physiol Regul Integr Comp Physiol 249: R643–R666, 1985. 4. Bidani AK, Schwartz MM, Lewis EF. Renal autoregulation and vulnerability to hypertensive injury in remnant kidney. Am J Physiol Renal Fluid Electrolyte Physiol 252: F1003–F1010, 1987. 5. Briggs JP, Schnermann J. Macula densa control of renin secretion and glomerular vascular tone: evidence for common cellular mechanisms. Renal Physiol 9: 193–203, 1986. 6. Cevese A, Guyton AC. Isohemic blood volume expansion in normal and areflexive dogs. Am J Physiol 231: 104 –111, 1976. 7. Che R, Yuan Y, Huang S, Zhang A. Mitochondrial dysfunction in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 306: F367–F378, 2014. 8. Chen J, Layton AT, Edwards A. A mathematical model of oxygen transport in the rat outer medulla: I. Model formulation and baseline results. Am J Physiol Renal Physiol 297: F517–F536, 2009. 9. Cowley AW Jr. Role of the renal medulla in volume and arterial pressure regulation. Am J Physiol Regul Integr Comp Physiol 273: R1–R15, 1997. 10. Cupples WA, Braam B. Assessment of renal autoregulation. Am J Physiol Renal Physiol 292: F1105–F1123, 2007. 11. Deng A, Tang T, Singh P, Wang C, Satriano J, Thomson SC, Blantz RC. Regulation of oxygen utilization by angiotensin II in chronic kidney disease. Kidney Int 75: 197–204, 2009. 12. Dengel DR, Goldberg AP, Mayuga RS, Kairis GM, Weir MR. Inslin resistance, elevated glomerular filtration fraction, and renal injury. Hypertension 28: 127–132, 1996. 13. Edwards A, Castrop H, Laghmani K, Vallon V, Layton AT. Regulation of NKCC2 isoform expression and NaCl transport in the thick ascending limb and macula densa cells. Am J Physiol Renal Physiol 307: F137–F146, 2014. 14. Edwards A, Layton AT. Calcium dynamics underlying the myogenic response of the renal afferent arteriole. Am J Physiol Renal Physiol 306: F34 –F48, 2014. 15. ERA-EDTA Registry. ERA-EDTA Registry Annual Report 2009. Amsterdam, The Netherlands: Academic Medical Center, Department of Medical Informatics, 2011. 16. Evans RG, Harrop GK, Ngo JP, Ow CP, O’Connor PM. Basal renal O2 consumption and the efficiency of O2 utilization for Na⫹ reabsorption. Am J Physiol Renal Physiol 306: F551–F561, 2014. 17. Franchini KG, Mattson DL, Cowley AW Jr. Vasopressin modulation of medullary blood flow and pressure-natriuresis-diuresis in the decerebrated rat. Am J Physiol Regul Integr Comp Physiol 272: R1472–R1479, 1997. 18. Fry BC, Edward A, Layton AT. Impacts of nitric oxide and superoxide on renal medullary oxygen transport and urine concentration. Am J Physiol Renal Physiol. First published January 28, 2015; 10.1152/ ajprenal.00600.2014.
19. Fry BC, Edward A, Sgouralis I, Layton AT. Impact of renal medullary three-dimensional architecture on oxygen transport. Am J Physiol Renal Physiol 307: F263–F272, 2014. 20. Fu Y, Hall JE, Lu D, Lin L, Manning RD Jr, Cheng L, GomezSanchez C, Juncos LA, Liu R. Aldosterone blunts tubuloglomerular feedback by activating macula densa mineralocorticoid receptors. Hypertension 59: 599 –606, 2012. 21. Garcia-Estañ J, Roman RJ. Role of renal interstitial hydrostatic pressure in the pressure diuresis response. Am J Physiol Renal Fluid Electrolyte Physiol 256: F63–F70, 1989. 22. Ge Y, Murphy SR, Fan F, Williams JM, Falck JR, Liu R, Roman RJ. Role of 20-HETE in the impaired myogenic and TGF responses of the Af-Art of Dahl salt-sensitive rats. Am J Physiol Renal Physiol 307: F509 –F515, 2014. 23. Granger JP. Pressure natriuresis. Role of renal interstitial hydrostatic pressure. Hypertension 19: I9 –17, 1992. 24. Granger JP, Alexander BT, Llinas M. Mechanisms of pressure natriuresis. Curr Hypertens Rep 4: 152–159, 2002. 25. Guyton AC, Coleman TG, Granger HJ. Circulation: Overall regulation. Annu Rev Physiol 34: 13–46, 1972. 26. Holstein-Rathlou NH, Sosnovtseva OV, Pavlov AN, Cupples WA, Sorensen CM, Marsh DJ. Nephron blood flow dynamics measured by laser speckle contrast imaging. Am J Physiol Renal Physiol 300: F319 – F329, 2011. 27. Holstein-Rathlou NH, Marsh DJ. Renal blood flow regulation and arterial pressure fluctuations: a case study in nonlinear dynamics. Physiol Rev 74: 637–681, 1994. 28. Hostetter TH, Rennke HG, Brenner BM. The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med 72: 375–380, 1982. 29. Huang CL, Cogan MG. Atrial natriuretic factor inhibits maximal tubuloglomerular feedback response. Am J Physiol Renal Fluid Electrolyte Physiol 252: F825–F828, 1987. 30. Hueper K, Hartung D, Gutberlet M, Gueler F, Sann H, Husen B, Wacker F, Reiche D. Assessment of impaired vascular reactivity in a rat model of diabetic nephropathy: effect of nitric oxide synthesis inhibition on intrarenal diffusion and oxygenation measured by magnetic resonance imaging. Am J Physiol Renal Physiol 305: F1428 –F1435, 2013. 31. Iwashima F, Yoshimoto T, Minami I, Sakurada M, Hirono Y, Hirata Y. Aldosterone induces superoxide generation via Rac1 activation in endothelial cells. Endocrinology 149: 1009 –1014, 2008. 32. Johnson PC. The myogenic response. In: Handbook of Physiology. The Cardiovascular System. Vascular Smooth Muscle. Bethesda, MD: Am. Physiol. Soc., 1981, sect. 2, vol. 2, p. 409 –442. 33. Just A. Mechanisms of renal blood flow autoregulation: dynamics and contributions. Am J Physiol Regul Integr Comp Physiol 292: R1–R17, 2007. 34. Just A, Arendhorst W. Nitric oxide blunts myogenic autoregulation in rat renal but not skeletal muscle circulation via tubuloglomerular feedback, J Physiol 569: 959 –974, 2005. 35. Kaloyanides GJ, DiBona GF, Raskin P. Pressure natriuresis in the isolated kidney. Am J Physiol 220: 1660 –1666, 1971. 36. Komers R, Anderson S. Glomerular endothelial NOS (eNOS) expression in type 2 diabetic patients with nephropathy. Nephrol Dial Transplant 23: 3037–3038, 2008. 37. Komers R, Anderson S. Paradoxes of nitric oxide in the diabetic kidney. Am J Physiol Renal Physiol 284: F1121–F1137, 2003. 38. Kriz W, Kaissling B. Structural organization of the mammalian kidney. In: The Kidney: Physiology and Pathophysiology (3 ed.). Philadelphia, PA: Lippincott Williams & Wilkins, 2000, p. 587–654. 39. Kurtz L, Madsen K, Kurt B, Jensen BL, Walter S, Banas B, Wagner C, Kurtz A. High-level connexin expression in the human juxtaglomerular apparatus. Nephron Physiol 116: p1–p8, 2010. 40. Legrand M, Almac E, Mik EG, Johannes T, Kandil A, Bezemer R, Payen D, Ince C. L-NIL prevents renal microvascular hypoxia and increase of renal oxygen consumption after ischemia-reperfusion in rats. Am J Physiol Renal Physiol 296: F1109 –F1117, 2009. 41. Legrand M, Kandil A, Payen D, Ince C. Effects of sepiapterin infusion on renal oxygenation and early acute renal injury after suprarenal aortic clamping in rats. J Cardiovasc Pharmacol 58: 192–198, 2011. 42. Liu R, Pittner J, Persson AE. Changes of cell volume and nitric oxide concentration in macula densa cells caused by changes in luminal NaCl concentration. J Am Soc Nephrol 13: 2688 –2696, 2002.
AJP-Renal Physiol • doi:10.1152/ajprenal.00008.2015 • www.ajprenal.org
Review RENAL HEMODYNAMICS 43. Liu R, Ren Y, Garvin JL, Carretero OA. Superoxide enhances tubuloglomerular feed-back by constricting the afferent arteriole. Kidney Int 66: 268 –274, 2004. 44. Loutzenhiser R, Bidani A, Chilton L. Renal myogenic response: kinetic attributes and physiologic role. Circ Res 90: 1316 –1324, 2002. 45. Loutzenhiser R, Bidani A, Wang X. Systolic pressure and the myogenic response of the renal afferent arteriole. Acta Physiol Scand 181: 404 –413, 2004. 46. Marsh DJ, Wexler AS, Brazhe A, Postnov DE, Sosnovtseva OV, Holstein-Rathlou NH. Multinephron dynamics on the renal vascular network. Am J Physiol Renal Physiol 304: F88 –F102, 2013. 47. Martino JA, Earley LE. Relationship between intrarenal hydrostatic pressure and hemodynamically induced changes in sodium excretion. Circ Res 23: 371–386, 1968. 48. Moss R, Layton AT. Dominant factors that govern pressure natriuresis in diuresis and antidiuresis: a mathematical model. Am J Physiol Renal Physiol 306: F952–F969, 2014. 49. Moss R, Thomas SR. Hormonal regulation of salt and water excretion: a mathematical model of whole kidney function and pressure natriuresis. Am J Physiol Renal Physiol 306: F224 –F248, 2014. 50. National Institute of Diabetes and Digestive and Kidney Diseases. U. S. Renal Data System, USRDS 2009 Annual Data Report. Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, 2009. 51. Neuhofer W, Beck FX. Cell survival in the hostile environment of the renal medulla. Annu Rev Physiol 67: 531–555, 2005. 52. Neuringer JR, Brenner BM. Hemodynamic theory of progressive renal disease: a 10-year update in brief review. Am J Kidney Dis 22: 98 –104, 1993. 53. Ogawa S, Lee TM, Kay AR, Tank DW. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci USA 87: 9868 –9872, 1990. 54. Oostendorp M, de Vries EE, Slenter JM, Peutz-Kootstra CJ, Snoeijs MG, Post MJ, van Heurn LW, Backes WH. MRI of renal oxygenation and function after normothermic ischemia-reperfusion injury. NMR Biomed 24: 194 –200, 2011. 55. Oppermann M, Carota I, Schiessl I, Eisner C, Castrop H, Schnermann J. Direct assessment of tubuloglomerular feedback responsiveness in connexin 40-deficient mice. Am J Physiol Renal Physiol 304: F1181– F1186, 2013. 56. Palm F, Fasching A, Hansell P, Kallskog O. Nitric oxide originating from NOS1 controls oxygen utilization and electrolyte transport efficiency in the diabetic kidney. Am J Physiol Renal Physiol 298: F416 –F420, 2010. 57. Pannabecker TL, Dantzler WH. Three-dimensional lateral and vertical relationship of inner medullary loops of Henle and collecting duct. Am J Physiol Renal Physiol 287: F767–F774, 2004. 58. Pannabecker TL, Dantzler WH. Three-dimensional architecture of inner medullary vasa recta. Am J Physiol Renal Physiol 290: F1355–F1366, 2006. 59. Pannabecker TL, Layton AT. Targeted delivery of solutes and oxygen in the renal medulla: role of microvessel architecture. Am J Physiol Renal Physiol 307: F649 –F655, 2014. 60. Patinha D, Fasching A, Pinho D, Albino-Teixeira A, Morato M, Palm F. Angiotensin II contributes to glomerular hyperfiltration in diabetic rats independently of adenosine type I receptors. Am J Physiol Renal Physiol 304: F614 –F622, 2013. 61. Pelayo JC, Westcott JY. Impaired autoregulation of glomerular capillary hydrostatic pressure in the rat remnant kidney nephron. J Clin Invest 88: 101–105, 1991. 62. Peti-Peterdi J. Calcium wave of tubuloglomerular feedback. Am J Physiol Renal Physiol 291: F473–F480, 2006. 63. Oostendorp M, de Vries EE, Slenter JM, Peutz-Kootstra CJ, Snoeijs MG, Post MJ, van Heurn LW, Backes WH. MRI of renal oxygenation and function after normothermic ischemia-reperfusion injury. NMR Biomed 24: 194 –200, 2011. 64. Ren Y, D’Ambrosio MA, Garvin JL, Peterson EL, Carretero OA. Mechanism of impaired afferent arteriole myogenic response in Dahl salt-sensitive rats: role of 20-HETE. Am J Physiol Renal Physiol 307: F533–F538, 2014. 65. Ren Y, Garvin JL, Liu R, Carretero OA. Role of macula densa adenosine triphosphate (ATP) in tubuloglomerular feedback. Kidney Int 66: 1479 –1485, 2004.
F955
66. Roman RJ, Cowley AW Jr, Garcia-Estañ J, Lombard JH. Pressurediuresis in volume-expanded rats. Cortical and medullary hemodynamics. Hypertension 12: 168 –176, 1988. 67. Roman RJ, Alonso-Galicia M, Wilson TW. Renal P450 metabolites of arachidonic acid and the development of hypertension in Dahl saltsensitive rats. Am J Hypertens 10: 63S–67S, 1997. 68. Roman RJ, Ma YH, Frohlich B, Markham B. Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. Hypertension 21: 985–988, 1993. 69. Romero JC, Knox FG. Mechanisms underlying pressure-related natriuresis: the role of the renin-angiotensin and prostaglandin systems. State of the art lecture. Hypertension 11: 724 –738, 1988. 70. Schiessl IM, Rosenauer A, Kattler V, Minuth WW, Oppermann M, Castrop H. Dietary salt intake modulates differential splicing of the Na-K-2Cl cotransporter NKCC2. Am J Physiol Renal Physiol 305: F1139 –F1148, 2013. 71. Sgouralis I, Layton AT. Theoretical assessment of renal autoregulatory mechanisms. Am J Physiol Renal Physiol 306: F1357–F1371, 2014. 72. Siegemund M, van Bommel J, Stegenga ME, Studer W, van Iterson M, Annaheim S, Mebazaa A, Ince C. Aortic cross-clamping and reperfusion in pigs reduces microvascular oxygenation by altered systemic and regional blood flow distribution. Anesth Analg 111: 345–353, 2010. 73. Singh P, Deng A, Blantz RC, Thomson SC. Unexpected effect of angiotensin AT1 blockade on tubuloglomerular feedback in early subtotal nephrectomy. Am J Physiol Renal Physiol 296: F1158 –F1165, 2009. 74. Singh P, Thomson SC. Salt sensitivity of tubuloglomerular feedback in the early remnant kidney. Am J Physiol Renal Physiol 306: F172–F180, 2014. 75. Sun D, Samuelson LC, Yang T, Huang Y, Paliege A, Saunders T, Briggs J, Schnermann J. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc Natl Acad Sci USA 98: 9983–9988, 2001. 76. Takenaka T, Inoue T, Kanno Y, Okada H, Meaney KR, Hill CE, Suzuki H. Expression and role of connexins in the rat renal vasculature. Kidney Int 73: 415–422, 2008. 77. Vallon V, Osswald H, Blantz RC, Thomson S. Potential role of luminal potassium in tubuglomerular feedback. J Am Soc Nephrol 8: 1831–1837, 1997. 78. Vallon V, Thomson SC. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu Rev Physiol 74: 351–375, 2012. 79. Weinstein AM. A mathematical model of rat ascending Henle limb. III. Tubular function. Am J Physiol Renal Physiol 298: F543–F556, 2010. 80. Weinstein AM, Krahn TA. A mathematical model of rat ascending Henle limb. II. Epithelial function. Am J Physiol Renal Physiol 298: F525–F542, 2010. 81. Welch WJ, Wilcox CS. Feedback responses during sequential inhibition of angiotensin and thromboxane. Am J Physiol Renal Fluid Electrolyte Physiol 258: F457–F466, 1990. 82. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27: 1047–1053, 2004. 83. Yuan J, Pannabecker TL. Architecture of inner medullary descending and ascending vasa recta: pathways for countercurrent exchange. Am J Physiol Renal Physiol 299: F265–F272, 2010. 84. Zhang W, Edwards A. A model of nitric oxide tubulovascular cross talk in a renal outer medullary cross section. Am J Physiol Renal Physiol 292: F711–F722, 2007. 85. Zhang J, Hill CE. Differential connexin expression in preglomerular and postglomerular vasculature: accentuation during diabetes. Kidney Int 68: 1171–1185, 2005. 86. Zhang JL, Morrell G, Rusinek H, Warner L, Vivier PH, Cheung AK, Lerman LO, Lee VS. Measurement of renal tissue oxygenation with blood oxygen level-dependent MRI and oxygen transit modeling. Am J Physiol Renal Physiol 306: F579 –F587, 2014. 87. Zhang Q, Lin L, Lu Y, Liu H, Duan Y, Zhu X, Zou C, Manning RD Jr, Liu R. Interaction between nitric oxide and superoxide in the macula densa in aldosterone-induced alterations of tubuloglomerular feedback. Am J Physiol Renal Physiol 304: F326 –F332, 2013. 88. Zhao HJ, Wang Cheng H S, Chang MZ, Takahashi T, Fogo AB, Breyer MD, Harris RC. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol 17: 2664 –2669, 2006.
AJP-Renal Physiol • doi:10.1152/ajprenal.00008.2015 • www.ajprenal.org
