ced/ca/crum(leeo) Il. 338-341 @LongmanGrwpUKLtdlS@O
Workshop on Regulation by Extracellular Ca2+ Collected by Dr E. F. Nemeth
Control of renin secretion by extracellular calcium J.C.S. FRAY Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Biology, Spelman College, Atlanta, Georgia, USA
Extracellular Ca2+ has been shown to have a powerful effect on renin secretion. The early wo* of Peart and collaborators provided the first positive evidence that lowering extracellular Ca2+ stimulated renin secretion [l]. Additional studies soon showed an inverse relationship between renin secretion and extracellular Ca2’ 121. These as well as other studies prompted the initial suggestion that Ca2+ is a primary signal which regulates the secretion of renin and that most, if not all other signals which regulate renin secretion do so through a pathway dependent on Ca2+ [3]. Several investigators have since reviewed the evidence supporting the role of extracellular Ca2+ in the control of renin secretion [4-7.1. Several studies also support the stretch receptor model of renin secretion which holds that, for the most part, secretagogues which stimulate renin secretion do so by lowering the influx of extracellular Ca2+ and by promoting the extrusion of cytoc;olic Ca2’ [7]. On the other hand, factors . which inhibit renin secretion do so by promoting the influx of extracellular Ca2’[7]. It has also been suggested that intracellular stores of Ca2+ play a role, but this remains to be clarified and defined further.
In every respect, an inverse relationship has been demonstrated between renin secretion and Ca2’. The initial studies defining the role of Ca2’ showed raising extracellular Ca2+ from 2.5 mM to 7.5 mM in the medium perfusing isolated kidneys caused little change in renin secretion, but lowering Ca2+ below 2.5 mh4 caused a sharp and significant increase [21. These early findings raised the possibility that it is only below 2.5 mM extracellular Ca2+ that renin secretion is sensitive to changes in extracellular Ca2’. This inverse relationship has also been demonstrated in isolated juxtaglomerular cells [8]. All of these early studies considered average changes of both renin secretion and Ca2’. Renin secretion also varies iuversely with Ca2+ uptake into cultured cells believed to be enriched with juxtaglomerular cells [9]. It is of particular interest to note that neurohormones known to inhibit reniu secretion also stimulated the uptake of extracellular Ca2+ extracellular Ca2’“~u~~gYZ.uZ$Z~’ YZ demonstrated au inverse relationship between cytosolic Ca2+ and renin secretion [lo]. The latter studies pointed to some interesting features of the inverse relationship. At lo-’ cytosolic Ca2’, reniu 339
340
secretion is inhibited to 60% of the resting level of 1.8 x 10e8 M. Above 10e7 Ca2+, the secretory response remains relatively insensitive to changes in cytosolic Ca2+, whereas below 10m7M Ca2’ it is Taken together, the available most sensitive. evidence suggests that the juxtaglomerular cells contain Ca2+ receptors on their surface membranes, and that these Ca2+ receptors are modified (or regulated) by several factors. Extracellular Ca2+ substrate for the Caz”‘pEzpz. be &ET:: demonstrated in the isolated perfused kidney [21, and most recently in afferent arteriolar cells believed Raising to be juxtaglomerular cells [26]. extracellular Ca2+ causes a transient rise in intracellular Ca2+ which is followed by a slow In addition, extracellular Ca2’ decline 1261. modifies the effects of several other factors [26], presumably by modifying the Ca2+ receptor. The above studies prompted the advance of a theory to explain the central role of Ca2+ in the regulation of renin secretion. The theory holds that the response of all factors which regulate renin secretion are modified by extracellular Ca2+ [7]. Of the many factors and pathways proposed to control burocepror and the renin secretion the neurohormonal pathways are most important. Interactions between these two pathways have also stimulated some interest and have pointed to the importance of extracellular Ca2+. Renal perfusion pressure has been regarded as the primary hemodynamic factor regulating the baroreceptor pathway. Admnergic neurohormones, angiotensin II and ADH have been acknowledged as representative classes of the neurohormonul pathway. The role of extracellular Ca2+ in the mediation of both pathways will be discussed below. Extracellular Ca2’ plays a coupling role in the transduction of raising renal perfusion pressure to inhibit renin secretion. Raising perfusion ressute 2? promotes the inflow of extracellular Ca . The inhibitory response of high renal perfusion pressure is absent in Ca2+-free medium and is blocked by verapamil in perfused kidneys [7]. EDTA also blocks the inhibitory response in intact dogs [ll]. These effects of perfusion pressure and the inflow of extracellular Ca2+ may be direct on the juxtaglomerular cells because stretching the cells
CELL CALCIUM
themselves inhibits renin secretion, and the response is blocked by verapamil [12]. These observations are consistent with the hypothesis that high perfusion pressure increases the membrane permeability to Ca2’ [7]. Ca2+-channel agonists such as BAY K 8644 and CGP 28392 cause dose-dependent inhibition of renin secretion [131. These agonists specifically o en the Ca2’ channels. ZL Removal of extracellular Ca renders the agonists ineffective. Low renal perfusion stimulates renin secretion by a mechanism influenced by extracellular Ca2’. Low pressure stimulates renin secretion by decreasing the inflow of extracellular Ca2+ into the juxtaglomerular cells [7]. Thus, raising extracellular Ca2’ renders low pressure less effective, and the effect of low pressure may be blunted by promoting Ca2’ influx with high I? [14]. Angiotensin II and ADH inhibit renin secretion by a mechanism which involves the inflow of extracellular Ca2’. Removal of extracellular Ca2+ renders angiotensin II ineffective [24]. Blockers of Ca2+ inflow from the extracellular space reverse the inhibitory effect of angiotensin II and ADH [25]. Direct demonstration of angiotensin II-induced inhibition of renin secretion, with an associated increase in Ca2+ inflow, has been demonstrated [9]. Angiotensin II has been shown to stimulate a transient rise in intracellular Ca2+ which is followed by a slow decline plus subsequent oscillations [26]. One interesting observation in the cells believed to be juxtaglomemlar cells is that the angiotensin II-induced rise in cytosolic Ca2+ in inhibited by CAMP [26]. If these latter experiments are confirmed then they will settle one controversial point in the interaction between CAMP and Ca2+ in the control of renin secretion. It has been argued that CAMP controls renin secretion by a mechanism parallel to that of Ca2’ [7]. On the other hand, there is evidence suggesting that CAMP controls renin secretion mainly by modulating cellular Ca2’ [7]. It has been demonstrated that factors which inhibit renin secretion by raising cytosolic Ca2+ (such as angiotensin II) are blocked by CAMP, and the stimulatory effects of CAMP are inhibited by factors which raise cytosolic Ca2’ [7]. But only recently has it been shown that the increased cytosolic Ca2+
CONTROL
OF RENIN SECRETION
BY EXTRACELLLJLAR
CALCIUM
341
induced by angiotensin II is suppressed by cAh4P [26]. Although simultaneous renin secretion was not measured in the latter studies, the data on Ca2’ are consistent with the stretch hypothesis which suggests that factors which control xenin secretion do so by mechanisms coupled to Ca2+ 171. Recent evidence has rovided some clues on the Y+ role of extracellular Ca in the control of renin secretion by chemosmotic mechanisms. The chemosmotic hypothesis holds that chemosmotic swelling is a prerequisite step for the secretion of renin (Park CS., Honeyman TW. and Fray JCS., unpublished observations). Therefore chemosmotic swelling, and consequent increase in renin secretion, has been demonstrated with a K+/H+- exchange ionophore (nigericin), a weak base (benzylamine), or hypo-osmoticity (Park CS., Honeyman TW. and Raising Fray JCS., un ublished observations). extracellular Ca E abolished the response of all three experimental manipulations, further supporting the view lhat extracellular Ca2+ by activating a Ca2+ receptor on the surface ’ membrane of the juxtagXomerular cell, plays a fundamental role in the control of renin secretion through most, if not all, In terms of a chemosmotic major pathways. mechanism, the evidence suggests that one possible mechanism of action of excess of Ca*+ is to prevent chemosmotic swelling at some step(s) along the secretory cascade. In summary, Ca*+ plays a key role in the control Lowering extracellular Ca2+ of main secretion. stimulates secretion presumably by (de)activating Ca2+ receptors in the surface membrane leading to a lowering of cytosolic Ca2+. Factors which stimulate renin secretion also lower cytosolic Ca2+, and those which inhibit secretion raise cytosolic Ca2+i It is as yet unclear whether all factors which modify renin secretion by modifying cytosolic Ca2+ also modulate the Ca*+ receptor.
References
Acknawledgements
26. Kmtz A. Penner R. (1989) 3423-3427.
Work from our laboratory has been funded by grants from NSF (#DCB 8521794) and NM (#HL33214). We thank Ms Marcia McGhee for secretarial assistance.
1. Peart WS. (1977)
Lancet, 2, 543-548.
2. Fray JCS.
Am. J. Physiol., 232, F377-F382.
(1977)
3. Fray JCS. (1980)
Cim. Res., 47,485-492.
4. Churchill PC. (1985) 5. Kurtz A. (1986) 6. Hacker&al 47, 1-12.
Am. J. Physiol., 249, F175-F184.
Klin. Wochenschr.,
E. Tuagner R. (1986)
64, 838-846. Mol. Cell. Endocrinol.,
7. Fray JCS. Park CS. Valentine AND. Rev., 8,53-93. 8. Fray JCS. Laumns NJ. (1981)
(1987)
I. Physiol..
Endocrine 320, 31-39.
9. Kuttz A. Pfeilschifter J. Hutter A. Buhrle C. (1986) Physiol.. 250, C563C571.
Am. J.
10. Park CS. Honeyman TW. Chung Es. Lee JS. Sigmon DH. Fray ICS. (1986) Am. J. Physiol., 251, F1055-F1062. 11. Abe Y. Yukimura T. Iwao T. Mori N. Okaham T. Yamamoto K. (1983) Jpn. J. Phamtacol., 33,627-633. 12. Fray JCS. Lush DJ. (1984) 19-23.
Hypertension,
2 (Suppl. I),
13. Matsumura Y. Uriu T. Shinyama H. Sasaki Y. Morimoto S. (1987) J. Pharmacol. Exp. Thetap., 241, 1000. 14. Fray JCS. Park CS. (1979) 15. Vandongen 471-479.
J. Physiol., 292, 363-372.
R. Peart WS. (1974)
CIin. Sci. Mol. Med., 47,
16. Matsumura Y. Miyawaki N. Sasaki Y. Morimoto S. (1985) J. Pharmacol. Exp. Therap., 233,782-787. 17. Opgenorth TJ. Z&r JE. (1983) 227, 144-149.
I. Pharmacol.
18. Buhrle CP. Nobiling R. Taugner R. (1985) Physiol., 249, F272-F281.
Exp. Therap., Am. J.
19. Buhrle CP. Scholz H. Hackenthal E. Nobiling R. Taughner R. (1986) Mol. Cell. Endocrinol., 45, 37-47. 20. Park CS. Sigmon DH. Han DS. Honeyman (1986) Am. J. Physiol., 251, R531R536. 21. Hatada E. Rubin RP. (1978)
TW. Fray JCS.
J. Physiol., 274, 367-379.
22. Logan AG. Tenyi I. Peat WS. Breathmach AS. Martin B. (1977) Proc. R. Sot. Lond. [Viol], 195, 327-342. 23. Laychock SG. Harada E. Rubin RP. (1979) Pharmacol., 28,3205-3211. 24. Vandongen 125-129.
R. Peart WS. (1974)
25. Park CS. Han DS. Fray JCS. F70-F-74.
B&hem.
Br. J. Pharmacol.,
50,
(1981)O Am. J.‘Physiol.,
240,
Proc. Natl. Acad. Sci. USA, 86,
Please send reprint requests to : Dr John CS. Fray, Department of Physiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Workshop on Regulation by Extracellular Ca2+ Collected by Dr E. F. Nemeth
Control of renin secretion by extracellular calcium J.C.S. FRAY Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Department of Biology, Spelman College, Atlanta, Georgia, USA
Extracellular Ca2+ has been shown to have a powerful effect on renin secretion. The early wo* of Peart and collaborators provided the first positive evidence that lowering extracellular Ca2+ stimulated renin secretion [l]. Additional studies soon showed an inverse relationship between renin secretion and extracellular Ca2’ 121. These as well as other studies prompted the initial suggestion that Ca2+ is a primary signal which regulates the secretion of renin and that most, if not all other signals which regulate renin secretion do so through a pathway dependent on Ca2+ [3]. Several investigators have since reviewed the evidence supporting the role of extracellular Ca2+ in the control of renin secretion [4-7.1. Several studies also support the stretch receptor model of renin secretion which holds that, for the most part, secretagogues which stimulate renin secretion do so by lowering the influx of extracellular Ca2+ and by promoting the extrusion of cytoc;olic Ca2’ [7]. On the other hand, factors . which inhibit renin secretion do so by promoting the influx of extracellular Ca2’[7]. It has also been suggested that intracellular stores of Ca2+ play a role, but this remains to be clarified and defined further.
In every respect, an inverse relationship has been demonstrated between renin secretion and Ca2’. The initial studies defining the role of Ca2’ showed raising extracellular Ca2+ from 2.5 mM to 7.5 mM in the medium perfusing isolated kidneys caused little change in renin secretion, but lowering Ca2+ below 2.5 mh4 caused a sharp and significant increase [21. These early findings raised the possibility that it is only below 2.5 mM extracellular Ca2+ that renin secretion is sensitive to changes in extracellular Ca2’. This inverse relationship has also been demonstrated in isolated juxtaglomerular cells [8]. All of these early studies considered average changes of both renin secretion and Ca2’. Renin secretion also varies iuversely with Ca2+ uptake into cultured cells believed to be enriched with juxtaglomerular cells [9]. It is of particular interest to note that neurohormones known to inhibit reniu secretion also stimulated the uptake of extracellular Ca2+ extracellular Ca2’“~u~~gYZ.uZ$Z~’ YZ demonstrated au inverse relationship between cytosolic Ca2+ and renin secretion [lo]. The latter studies pointed to some interesting features of the inverse relationship. At lo-’ cytosolic Ca2’, reniu 339
340
secretion is inhibited to 60% of the resting level of 1.8 x 10e8 M. Above 10e7 Ca2+, the secretory response remains relatively insensitive to changes in cytosolic Ca2+, whereas below 10m7M Ca2’ it is Taken together, the available most sensitive. evidence suggests that the juxtaglomerular cells contain Ca2+ receptors on their surface membranes, and that these Ca2+ receptors are modified (or regulated) by several factors. Extracellular Ca2+ substrate for the Caz”‘pEzpz. be &ET:: demonstrated in the isolated perfused kidney [21, and most recently in afferent arteriolar cells believed Raising to be juxtaglomerular cells [26]. extracellular Ca2+ causes a transient rise in intracellular Ca2+ which is followed by a slow In addition, extracellular Ca2’ decline 1261. modifies the effects of several other factors [26], presumably by modifying the Ca2+ receptor. The above studies prompted the advance of a theory to explain the central role of Ca2+ in the regulation of renin secretion. The theory holds that the response of all factors which regulate renin secretion are modified by extracellular Ca2+ [7]. Of the many factors and pathways proposed to control burocepror and the renin secretion the neurohormonal pathways are most important. Interactions between these two pathways have also stimulated some interest and have pointed to the importance of extracellular Ca2+. Renal perfusion pressure has been regarded as the primary hemodynamic factor regulating the baroreceptor pathway. Admnergic neurohormones, angiotensin II and ADH have been acknowledged as representative classes of the neurohormonul pathway. The role of extracellular Ca2+ in the mediation of both pathways will be discussed below. Extracellular Ca2’ plays a coupling role in the transduction of raising renal perfusion pressure to inhibit renin secretion. Raising perfusion ressute 2? promotes the inflow of extracellular Ca . The inhibitory response of high renal perfusion pressure is absent in Ca2+-free medium and is blocked by verapamil in perfused kidneys [7]. EDTA also blocks the inhibitory response in intact dogs [ll]. These effects of perfusion pressure and the inflow of extracellular Ca2+ may be direct on the juxtaglomerular cells because stretching the cells
CELL CALCIUM
themselves inhibits renin secretion, and the response is blocked by verapamil [12]. These observations are consistent with the hypothesis that high perfusion pressure increases the membrane permeability to Ca2’ [7]. Ca2+-channel agonists such as BAY K 8644 and CGP 28392 cause dose-dependent inhibition of renin secretion [131. These agonists specifically o en the Ca2’ channels. ZL Removal of extracellular Ca renders the agonists ineffective. Low renal perfusion stimulates renin secretion by a mechanism influenced by extracellular Ca2’. Low pressure stimulates renin secretion by decreasing the inflow of extracellular Ca2+ into the juxtaglomerular cells [7]. Thus, raising extracellular Ca2’ renders low pressure less effective, and the effect of low pressure may be blunted by promoting Ca2’ influx with high I? [14]. Angiotensin II and ADH inhibit renin secretion by a mechanism which involves the inflow of extracellular Ca2’. Removal of extracellular Ca2+ renders angiotensin II ineffective [24]. Blockers of Ca2+ inflow from the extracellular space reverse the inhibitory effect of angiotensin II and ADH [25]. Direct demonstration of angiotensin II-induced inhibition of renin secretion, with an associated increase in Ca2+ inflow, has been demonstrated [9]. Angiotensin II has been shown to stimulate a transient rise in intracellular Ca2+ which is followed by a slow decline plus subsequent oscillations [26]. One interesting observation in the cells believed to be juxtaglomemlar cells is that the angiotensin II-induced rise in cytosolic Ca2+ in inhibited by CAMP [26]. If these latter experiments are confirmed then they will settle one controversial point in the interaction between CAMP and Ca2+ in the control of renin secretion. It has been argued that CAMP controls renin secretion by a mechanism parallel to that of Ca2’ [7]. On the other hand, there is evidence suggesting that CAMP controls renin secretion mainly by modulating cellular Ca2’ [7]. It has been demonstrated that factors which inhibit renin secretion by raising cytosolic Ca2+ (such as angiotensin II) are blocked by CAMP, and the stimulatory effects of CAMP are inhibited by factors which raise cytosolic Ca2’ [7]. But only recently has it been shown that the increased cytosolic Ca2+
CONTROL
OF RENIN SECRETION
BY EXTRACELLLJLAR
CALCIUM
341
induced by angiotensin II is suppressed by cAh4P [26]. Although simultaneous renin secretion was not measured in the latter studies, the data on Ca2’ are consistent with the stretch hypothesis which suggests that factors which control xenin secretion do so by mechanisms coupled to Ca2+ 171. Recent evidence has rovided some clues on the Y+ role of extracellular Ca in the control of renin secretion by chemosmotic mechanisms. The chemosmotic hypothesis holds that chemosmotic swelling is a prerequisite step for the secretion of renin (Park CS., Honeyman TW. and Fray JCS., unpublished observations). Therefore chemosmotic swelling, and consequent increase in renin secretion, has been demonstrated with a K+/H+- exchange ionophore (nigericin), a weak base (benzylamine), or hypo-osmoticity (Park CS., Honeyman TW. and Raising Fray JCS., un ublished observations). extracellular Ca E abolished the response of all three experimental manipulations, further supporting the view lhat extracellular Ca2+ by activating a Ca2+ receptor on the surface ’ membrane of the juxtagXomerular cell, plays a fundamental role in the control of renin secretion through most, if not all, In terms of a chemosmotic major pathways. mechanism, the evidence suggests that one possible mechanism of action of excess of Ca*+ is to prevent chemosmotic swelling at some step(s) along the secretory cascade. In summary, Ca*+ plays a key role in the control Lowering extracellular Ca2+ of main secretion. stimulates secretion presumably by (de)activating Ca2+ receptors in the surface membrane leading to a lowering of cytosolic Ca2+. Factors which stimulate renin secretion also lower cytosolic Ca2+, and those which inhibit secretion raise cytosolic Ca2+i It is as yet unclear whether all factors which modify renin secretion by modifying cytosolic Ca2+ also modulate the Ca*+ receptor.
References
Acknawledgements
26. Kmtz A. Penner R. (1989) 3423-3427.
Work from our laboratory has been funded by grants from NSF (#DCB 8521794) and NM (#HL33214). We thank Ms Marcia McGhee for secretarial assistance.
1. Peart WS. (1977)
Lancet, 2, 543-548.
2. Fray JCS.
Am. J. Physiol., 232, F377-F382.
(1977)
3. Fray JCS. (1980)
Cim. Res., 47,485-492.
4. Churchill PC. (1985) 5. Kurtz A. (1986) 6. Hacker&al 47, 1-12.
Am. J. Physiol., 249, F175-F184.
Klin. Wochenschr.,
E. Tuagner R. (1986)
64, 838-846. Mol. Cell. Endocrinol.,
7. Fray JCS. Park CS. Valentine AND. Rev., 8,53-93. 8. Fray JCS. Laumns NJ. (1981)
(1987)
I. Physiol..
Endocrine 320, 31-39.
9. Kuttz A. Pfeilschifter J. Hutter A. Buhrle C. (1986) Physiol.. 250, C563C571.
Am. J.
10. Park CS. Honeyman TW. Chung Es. Lee JS. Sigmon DH. Fray ICS. (1986) Am. J. Physiol., 251, F1055-F1062. 11. Abe Y. Yukimura T. Iwao T. Mori N. Okaham T. Yamamoto K. (1983) Jpn. J. Phamtacol., 33,627-633. 12. Fray JCS. Lush DJ. (1984) 19-23.
Hypertension,
2 (Suppl. I),
13. Matsumura Y. Uriu T. Shinyama H. Sasaki Y. Morimoto S. (1987) J. Pharmacol. Exp. Thetap., 241, 1000. 14. Fray JCS. Park CS. (1979) 15. Vandongen 471-479.
J. Physiol., 292, 363-372.
R. Peart WS. (1974)
CIin. Sci. Mol. Med., 47,
16. Matsumura Y. Miyawaki N. Sasaki Y. Morimoto S. (1985) J. Pharmacol. Exp. Therap., 233,782-787. 17. Opgenorth TJ. Z&r JE. (1983) 227, 144-149.
I. Pharmacol.
18. Buhrle CP. Nobiling R. Taugner R. (1985) Physiol., 249, F272-F281.
Exp. Therap., Am. J.
19. Buhrle CP. Scholz H. Hackenthal E. Nobiling R. Taughner R. (1986) Mol. Cell. Endocrinol., 45, 37-47. 20. Park CS. Sigmon DH. Han DS. Honeyman (1986) Am. J. Physiol., 251, R531R536. 21. Hatada E. Rubin RP. (1978)
TW. Fray JCS.
J. Physiol., 274, 367-379.
22. Logan AG. Tenyi I. Peat WS. Breathmach AS. Martin B. (1977) Proc. R. Sot. Lond. [Viol], 195, 327-342. 23. Laychock SG. Harada E. Rubin RP. (1979) Pharmacol., 28,3205-3211. 24. Vandongen 125-129.
R. Peart WS. (1974)
25. Park CS. Han DS. Fray JCS. F70-F-74.
B&hem.
Br. J. Pharmacol.,
50,
(1981)O Am. J.‘Physiol.,
240,
Proc. Natl. Acad. Sci. USA, 86,
Please send reprint requests to : Dr John CS. Fray, Department of Physiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
