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Curr Hypertens Rep. Author manuscript; available in PMC 2017 August 31. Published in final edited form as: Curr Hypertens Rep. 2016 August ; 18(8): 63. doi:10.1007/s11906-016-0668-z.
Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension Xiao C. Li1 and Jia L. Zhuo1 1Laboratory
of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, 2500 North State Street, Jackson, MS 39216-4505, USA
Author Manuscript
Abstract
Author Manuscript
It is well recognized that the renin-angiotensin system (RAS) exists not only as circulating, paracrine (cell to cell), but also intracrine (intracellular) system. In the kidney, however, it is difficult to dissect the respective contributions of circulating RAS versus intrarenal RAS to the physiological regulation of proximal tubular Na+ reabsorption and hypertension. Here, we review recent studies to provide an update in this research field with a focus on the proximal tubular RAS in angiotensin II (ANG II)-induced hypertension. Careful analysis of available evidence supports the hypothesis that both local synthesis or formation and AT1 (AT1a) receptor-and/or megalinmediated uptake of angiotensinogen (AGT), ANG I and ANG II contribute to high levels of ANG II in the proximal tubules of the kidney. Under physiological conditions, nearly all major components of the RAS including AGT, prorenin, renin, ANG I, and ANG II would be filtered by the glomerulus and taken up by the proximal tubules. In ANG II-dependent hypertension, the expression of AGT, prorenin, and (pro)renin receptors, and angiotensin-converting enzyme (ACE) is upregulated rather than downregulated in the kidney. Furthermore, hypertension damages the glomerular filtration barrier, which augments the filtration of circulating AGT, prorenin, renin, ANG I, and ANG II and their uptake in the proximal tubules. Together, increased local ANG II formation and augmented uptake of circulating ANG II in the proximal tubules, via activation of AT1 (AT1a) receptors and Na+/H+ ex-changer 3, may provide a powerful feedforward mechanism for promoting Na+ retention and the development of ANG II-induced hypertension.
Keywords Angiotensin II; Hypertension; Kidney; Megalin; Proximal tubule
Author Manuscript
Introduction High blood pressure, i.e., hypertension, is one of the most important courses of cardiovascular diseases, stroke, and chronic renal failure [1–3]. The impact and significance of hypertension in humans are best recognized by the facts that one in three US adults will
Correspondence to: Jia L. Zhuo. Compliance with Ethical Standards Conflict of Interest Drs. Li and Zhuo declare no conflicts of interest relevant to this manuscript. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Li and Zhuo
Page 2
Author Manuscript Author Manuscript
eventually develop hypertension or take antihypertensive drugs in their lifetime, and that economically, prevention and treatment of hypertension cost US$>100 billion a year [1–3]. The prevalence of hypertension in Americans aged 60 or older is much higher with over 65 % of this population having high blood pressure, accordingly to National Heart Lung Blood Institute (NHLBI). It is surprising, however, that only one in two of hypertensive patients have their blood pressure under adequate control with current antihypertensive drugs [1, 2, 4, 5]. The mechanisms underlying the development and progression of hypertension and the reasons underlying the difficulty in controlling hypertension in some hypertensive patients remain incompletely understood [1, 5, 6]. It is now well accepted that genetics, endocrine disorders, dietary, lifestyle, as well as environmental factors, all independently contribute to the development of hypertension. Yet, accordingly to NHLBI, the known genetic factors for hypertension may only account for
Curr Hypertens Rep. Author manuscript; available in PMC 2017 August 31. Published in final edited form as: Curr Hypertens Rep. 2016 August ; 18(8): 63. doi:10.1007/s11906-016-0668-z.
Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension Xiao C. Li1 and Jia L. Zhuo1 1Laboratory
of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, 2500 North State Street, Jackson, MS 39216-4505, USA
Author Manuscript
Abstract
Author Manuscript
It is well recognized that the renin-angiotensin system (RAS) exists not only as circulating, paracrine (cell to cell), but also intracrine (intracellular) system. In the kidney, however, it is difficult to dissect the respective contributions of circulating RAS versus intrarenal RAS to the physiological regulation of proximal tubular Na+ reabsorption and hypertension. Here, we review recent studies to provide an update in this research field with a focus on the proximal tubular RAS in angiotensin II (ANG II)-induced hypertension. Careful analysis of available evidence supports the hypothesis that both local synthesis or formation and AT1 (AT1a) receptor-and/or megalinmediated uptake of angiotensinogen (AGT), ANG I and ANG II contribute to high levels of ANG II in the proximal tubules of the kidney. Under physiological conditions, nearly all major components of the RAS including AGT, prorenin, renin, ANG I, and ANG II would be filtered by the glomerulus and taken up by the proximal tubules. In ANG II-dependent hypertension, the expression of AGT, prorenin, and (pro)renin receptors, and angiotensin-converting enzyme (ACE) is upregulated rather than downregulated in the kidney. Furthermore, hypertension damages the glomerular filtration barrier, which augments the filtration of circulating AGT, prorenin, renin, ANG I, and ANG II and their uptake in the proximal tubules. Together, increased local ANG II formation and augmented uptake of circulating ANG II in the proximal tubules, via activation of AT1 (AT1a) receptors and Na+/H+ ex-changer 3, may provide a powerful feedforward mechanism for promoting Na+ retention and the development of ANG II-induced hypertension.
Keywords Angiotensin II; Hypertension; Kidney; Megalin; Proximal tubule
Author Manuscript
Introduction High blood pressure, i.e., hypertension, is one of the most important courses of cardiovascular diseases, stroke, and chronic renal failure [1–3]. The impact and significance of hypertension in humans are best recognized by the facts that one in three US adults will
Correspondence to: Jia L. Zhuo. Compliance with Ethical Standards Conflict of Interest Drs. Li and Zhuo declare no conflicts of interest relevant to this manuscript. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Li and Zhuo
Page 2
Author Manuscript Author Manuscript
eventually develop hypertension or take antihypertensive drugs in their lifetime, and that economically, prevention and treatment of hypertension cost US$>100 billion a year [1–3]. The prevalence of hypertension in Americans aged 60 or older is much higher with over 65 % of this population having high blood pressure, accordingly to National Heart Lung Blood Institute (NHLBI). It is surprising, however, that only one in two of hypertensive patients have their blood pressure under adequate control with current antihypertensive drugs [1, 2, 4, 5]. The mechanisms underlying the development and progression of hypertension and the reasons underlying the difficulty in controlling hypertension in some hypertensive patients remain incompletely understood [1, 5, 6]. It is now well accepted that genetics, endocrine disorders, dietary, lifestyle, as well as environmental factors, all independently contribute to the development of hypertension. Yet, accordingly to NHLBI, the known genetic factors for hypertension may only account for
