Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Clinical and Experimental Nephrology
Published in: Clinical and Experimental Nephrology 1/2012

01-02-2012 | Review Article

Convergence of major physiological stimuli for renin release on the Gs-alpha/cyclic adenosine monophosphate signaling pathway

Authors: Soo Mi Kim, Josephine P. Briggs, Jurgen Schnermann

Published in: Clinical and Experimental Nephrology | Issue 1/2012

Login to get access

Abstract

Control of the renin system by physiological mechanisms such as the baroreceptor or the macula densa (MD) is characterized by asymmetry in that the capacity for renin secretion and expression to increase is much larger than the magnitude of the inhibitory response. The large stimulatory reserve of the renin–angiotensin system may be one of the causes for the remarkable salt-conserving power of the mammalian kidney. Physiological stimulation of renin secretion and expression relies on the activation of regulatory pathways that converge on the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway. Mice with selective Gs-alpha (Gsα) deficiency in juxtaglomerular granular cells show a marked reduction of basal renin secretion, and an almost complete unresponsiveness of renin release to furosemide, hydralazine, or isoproterenol. Cyclooxygenase-2 generating prostaglandin E2 (PGE2) and prostacyclin (PGI2) in MD and thick ascending limb cells is one of the main effector systems utilizing Gsα-coupled receptors to stimulate the renin–angiotensin system. In addition, β-adrenergic receptors are critical for the expression of high basal levels of renin and for its release response to lowering blood pressure or MD sodium chloride concentration. Nitric oxide generated by nitric oxide synthases in the MD and in endothelial cells enhances cAMP-dependent signaling by stabilizing cAMP through cyclic guanosine monophosphate-dependent inhibition of phosphodiesterase 3. The stimulation of renin secretion by drugs that inhibit angiotensin II formation or action results from the convergent activation of cAMP probably through indirect augmentation of the activity of PGE2 and PGI2 receptors, β-adrenergic receptors, and nitric oxide.
Literature
1.
Kirchheim HR, Ehmke H, Hackenthal E, Lowe W, Persson P. Autoregulation of renal blood flow, glomerular filtration rate and renin release in conscious dogs. Pflugers Arch. 1987;410:441–9.PubMedCrossRef
2.
He XR, Greenberg SG, Briggs JP, Schnermann J. Effects of furosemide and verapamil on the NaCl dependency of macula densa-mediated renin secretion. Hypertension. 1995;26:137–42.PubMed
3.
Chen L, Kim SM, Oppermann M, Faulhaber-Walter R, Huang Y, Mizel D, et al. Regulation of renin in mice with Cre recombinase-mediated deletion of G protein Gsalpha in juxtaglomerular cells. Am J Physiol Renal Physiol. 2007;292:F27–37.PubMedCrossRef
4.
Neubauer B, Machura K, Chen M, Weinstein LS, Oppermann M, Sequeira-Lopez ML, et al. Development of vascular renin expression in the kidney critically depends on the cyclic AMP pathway. Am J Physiol Renal Physiol. 2009;296:F1006–12.PubMedCrossRef
5.
Chen M, Gavrilova O, Liu J, Xie T, Deng C, Nguyen AT, et al. Alternative Gnas gene products have opposite effects on glucose and lipid metabolism. Proc Natl Acad Sci USA. 2005;102:7386–91.PubMedCrossRef
6.
Sequeira Lopez ML, Pentz ES, Nomasa T, Smithies O, Gomez RA. Renin cells are precursors for multiple cell types that switch to the renin phenotype when homeostasis is threatened. Dev Cell. 2004;6:719–28.PubMedCrossRef
7.
Larsson C, Weber P, Anggard E. Arachidonic acid increases and indomethacin decreases plasma renin activity in the rabbit. Eur J Pharmacol. 1974;28:391–4.PubMedCrossRef
8.
Keeton TK, Campbell WB. The pharmacologic alteration of renin release. Pharmacol Rev. 1980;32:81–227.PubMed
9.
Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. 1994;94:2504–10.PubMedCrossRef
10.
Theilig F, Campean V, Paliege A, Breyer M, Briggs JP, Schnermann J, Bachmann S. Epithelial COX-2 expression is not regulated by nitric oxide in rodent renal cortex. Hypertension. 2002;39:848–53.PubMedCrossRef
11.
Vio CP, Cespedes C, Gallardo P, Masferrer JL. Renal identification of cyclooxygenase-2 in a subset of thick ascending limb cells. Hypertension. 1997;30:687–92.PubMed
12.
Mangat H, Peterson LN, Burns KD. Hypercalcemia stimulates expression of intrarenal phospholipase A2 and prostaglandin H synthase-2 in rats. J Clin Invest. 1997;100:1941–50.PubMedCrossRef
13.
Cheng HF, Wang JL, Zhang MZ, Miyazaki Y, Ichikawa I, McKanna JA, Harris RC. Angiotensin II attenuates renal cortical cyclooxygenase-2 expression. J Clin Invest. 1999;103:953–61.PubMedCrossRef
14.
Fuson AL, Komlosi P, Unlap TM, Bell PD, Peti-Peterdi J. Immunolocalization of a microsomal prostaglandin E synthase in rabbit kidney. Am J Physiol Renal Physiol. 2003;285:F558–64.PubMed
15.
Campean V, Theilig F, Paliege A, Breyer M, Bachmann S. Key enzymes for renal prostaglandin synthesis: site-specific expression in rodent kidney (rat, mouse). Am J Physiol Renal Physiol. 2003;285:F19–32.PubMed
16.
Greenberg SG, Lorenz JN, He XR, Schnermann JB, Briggs JP. Effect of prostaglandin synthesis inhibition on macula densa-stimulated renin secretion. Am J Physiol Renal Physiol. 1993;265:F578–83.
17.
Traynor TR, Smart A, Briggs JP, Schnermann J. Inhibition of macula densa-stimulated renin secretion by pharmacological blockade of cyclooxygenase-2. Am J Physiol Renal Physiol. 1999;277:F706–10.
18.
Peti-Peterdi J, Komlosi P, Fuson AL, Guan Y, Schneider A, Qi Z, et al. Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells. J Clin Invest. 2003;112:76–82.PubMed
19.
Bailie MD, Crosslan K, Hook JB. Natriuretic effect of furosemide after inhibition of prostaglandin synthetase. J Pharmacol Exp Ther. 1976;199:469–76.PubMed
20.
Francisco LL, Osborn JL, DiBona GF. Prostaglandins in renin release during sodium deprivation. Am J Physiol Renal Physiol. 1982;243:F537–42.
21.
Schricker K, Hamann M, Kurtz A. Nitric oxide and prostaglandins are involved in the macula densa control of the renin system. Am J Physiol Renal Physiol. 1995;269:F825–30.
22.
Kammerl MC, Nusing RM, Richthammer W, Kramer BK, Kurtz A. Inhibition of COX-2 counteracts the effects of diuretics in rats. Kidney Int. 2001;60:1684–91.PubMedCrossRef
23.
Reinalter SC, Jeck N, Brochhausen C, Watzer B, Nusing RM, Seyberth HW, Komhoff M. Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int. 2002;62:253–60.PubMedCrossRef
24.
Jackson EK, Gerkens JF, Brash AR, Branch RA. Acute renal artery constriction increases renal prostaglandin I2 biosynthesis and renin release in the conscious dog. J Pharmacol Exp Ther. 1982;222:410–3.PubMed
25.
Data JL, Gerber JG, Crump WJ, Frolich JC, Hollifield JW, Nies AS. The prostaglandin system. A role in canine baroreceptor control of renin release. Circ Res. 1978;42:454–8.PubMed
26.
Fujino T, Nakagawa N, Yuhki K, Hara A, Yamada T, Takayama K, et al. Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP. J Clin Invest. 2004;114:805–12.PubMed
27.
Yang T, Park JM, Arend L, Huang Y, Topaloglu R, Pasumarthy A, et al. Low chloride stimulation of prostaglandin E2 release and cyclooxygenase-2 expression in a mouse macula densa cell line. J Biol Chem. 2000;275:37922–9.PubMedCrossRef
28.
Cheng HF, Wang JL, Zhang MZ, McKanna JA, Harris RC. Role of p38 in the regulation of renal cortical cyclooxygenase-2 expression by extracellular chloride. J Clin Invest. 2000;106:681–8.PubMedCrossRef
29.
Cheng HF, Harris RC. Cyclooxygenase-2 expression in cultured cortical thick ascending limb of Henle increases in response to decreased extracellular ionic content by both transcriptional and post-transcriptional mechanisms. Role of p38-mediated pathways. J Biol Chem. 2002;277:45638–43.PubMedCrossRef
30.
Guan Z, Buckman SY, Miller BW, Springer LD, Morrison AR. Interleukin-1beta-induced cyclooxygenase-2 expression requires activation of both c-Jun NH2-terminal kinase and p38 MAPK signal pathways in rat renal mesangial cells. J Biol Chem. 1998;273:28670–6.PubMedCrossRef
31.
Yang T, Huang Y, Heasley LE, Berl T, Schnermann JB, Briggs JP. MAPK mediation of hypertonicity-stimulated cyclooxygenase-2 expression in renal medullary collecting duct cells. J Biol Chem. 2000;275:23281–6.PubMedCrossRef
32.
Xie W, Herschman HR. Transcriptional regulation of prostaglandin synthase 2 gene expression by platelet-derived growth factor and serum. J Biol Chem. 1996;271:31742–8.PubMedCrossRef
33.
Kim SM, Chen L, Mizel D, Huang YG, Briggs JP, Schnermann J. Low plasma renin and reduced renin secretory responses to acute stimuli in conscious COX-2-deficient mice. Am J Physiol Renal Physiol. 2007;292:F415–22.PubMedCrossRef
34.
Yang T, Endo Y, Huang YG, Smart A, Briggs JP, Schnermann J. Renin expression in COX-2-knockout mice on normal or low-salt diets. Am J Physiol Renal Physiol. 2000;279:F819–25.PubMed
35.
Cheng HF, Wang JL, Zhang MZ, Wang SW, McKanna JA, Harris RC. Genetic deletion of COX-2 prevents increased renin expression in response to ACE inhibition. Am J Physiol Renal Physiol. 2001;280:F449–56.PubMed
36.
Hocherl K, Kammerl MC, Schumacher K, Endemann D, Grobecker HF, Kurtz A. Role of prostanoids in regulation of the renin–angiotensin–aldosterone system by salt intake. Am J Physiol Renal Physiol. 2002;283:F294–301.PubMed
37.
Kammerl MC, Nusing RM, Seyberth HW, Riegger GA, Kurtz A, Kramer BK. Inhibition of cyclooxygenase-2 attenuates urinary prostanoid excretion without affecting renal renin expression. Pflugers Arch. 2001;442:842–7.PubMedCrossRef
38.
Kopp U, DiBona GF. Interaction of renal beta 1-adrenoceptors and prostaglandins in reflex renin release. Am J Physiol. 1983;244:F418–24.PubMed
39.
Mundel P, Bachmann S, Bader M, Fischer A, Kummer W, Mayer B, Kriz W. Expression of nitric oxide synthase in kidney macula densa cells. Kidney Int. 1992;42:1017–9.PubMedCrossRef
40.
Wilcox CS, Welch WJ, Murad F, Gross SS, Taylor G, Levi R, Schmidt HH. Nitric oxide synthase in macula densa regulates glomerular capillary pressure. Proc Natl Acad Sci USA. 1992;89:11993–7.PubMedCrossRef
41.
He XR, Greenberg SG, Briggs JP, Schnermann JB. Effect of nitric oxide on renin secretion. II. Studies in the perfused juxtaglomerular apparatus. Am J Physiol Renal Physiol. 1995;268:F953–9.
42.
Chatziantoniou C, Pauti MD, Pinet F, Promeneur D, Dussaule JC, Ardaillou R. Regulation of renin release is impaired after nitric oxide inhibition. Kidney Int. 1996;49:626–33.PubMedCrossRef
43.
Beierwaltes WH. Selective neuronal nitric oxide synthase inhibition blocks furosemide-stimulated renin secretion in vivo. Am J Physiol Renal Physiol. 1995;269:F134–9.
44.
Reid IA, Chou L. Effect of blockade of nitric oxide synthesis on the renin secretory response to frusemide in conscious rabbits. Clin Sci (Colch). 1995;88:657–63.
45.
Castrop H, Schweda F, Mizel D, Huang Y, Briggs J, Kurtz A, Schnermann J. Permissive role of nitric oxide in macula densa control of renin secretion. Am J Physiol Renal Physiol. 2004;286:F848–57.PubMedCrossRef
46.
Persson PB, Baumann JE, Ehmke H, Hackenthal E, Kirchheim HR, Nafz B. Endothelium-derived NO stimulates pressure-dependent renin release in conscious dogs. Am J Physiol. 1993;264:F943–7.PubMed
47.
Scholz H, Kurtz A. Involvement of endothelium-derived relaxing factor in the pressure control of renin secretion from isolated perfused kidney. J Clin Invest. 1993;91:1088–94.PubMedCrossRef
48.
Harrison SA, Reifsnyder DH, Gallis B, Cadd GG, Beavo JA. Isolation and characterization of bovine cardiac muscle cGMP-inhibited phosphodiesterase: a receptor for new cardiotonic drugs. Mol Pharmacol. 1986;29:506–14.PubMed
49.
Chiu T, Reid IA. Role of cyclic GMP-inhibitable phosphodiesterase and nitric oxide in the beta adrenoceptor control of renin secretion. J Pharmacol Exp Ther. 1996;278:793–9.PubMed
50.
Kurtz A, Gotz KH, Hamann M, Kieninger M, Wagner C. Stimulation of renin secretion by NO donors is related to the cAMP pathway. Am J Physiol Renal Physiol. 1998;274:F709–17.
51.
Kurtz A, Gotz KH, Hamann M, Wagner C. Stimulation of renin secretion by nitric oxide is mediated by phosphodiesterase 3. Proc Natl Acad Sci USA. 1998;95:4743–7.PubMedCrossRef
52.
Friis UG, Jensen BL, Sethi S, Andreasen D, Hansen PB, Skott O. Control of renin secretion from rat juxtaglomerular cells by cAMP-specific phosphodiesterases. Circ Res. 2002;90:996–1003.PubMedCrossRef
53.
Sayago CM, Beierwaltes WH. Nitric oxide synthase and cGMP-mediated stimulation of renin secretion. Am J Physiol Regul Integr Comp Physiol. 2001;281:R1146–51.PubMed
54.
Beierwaltes WH, Carretero OA. Nonprostanoid endothelium-derived factors inhibit renin release. Hypertension. 1992;19:II68–73.PubMed
55.
Vidal MJ, Romero JC, Vanhoutte PM. Endothelium-derived relaxing factor inhibits renin release. Eur J Pharmacol. 1988;149:401–2.PubMedCrossRef
56.
Gambaryan S, Wagner C, Smolenski A, Walter U, Poller W, Haase W, Kurtz A, Lohmann SM. Endogenous or overexpressed cGMP-dependent protein kinases inhibit cAMP-dependent renin release from rat isolated perfused kidney, microdissected glomeruli, and isolated juxtaglomerular cells. Proc Natl Acad Sci USA. 1998;95:9003–8.PubMedCrossRef
57.
DiBona GF, Kopp U. Neural control of renal function. In: Seldin DW, Giebisch G, editors. The kidney, physiology and pathophysiology, vol. 1. Philadelphia: Lippincott, Williams & Wilkins; 2001.
58.
Boivin V, Jahns R, Gambaryan S, Ness W, Boege F, Lohse MJ. Immunofluorescent imaging of beta 1- and beta 2-adrenergic receptors in rat kidney. Kidney Int. 2001;59:515–31.PubMedCrossRef
59.
Rohrer DK, Chruscinski A, Schauble EH, Bernstein D, Kobilka BK. Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors. J Biol Chem. 1999;274:16701–8.PubMedCrossRef
60.
Rohrer DK, Kobilka BK. Insights from in vivo modification of adrenergic receptor gene expression. Annu Rev Pharmacol Toxicol. 1998;38:351–73.PubMedCrossRef
61.
Kim SM, Chen L, Faulhaber-Walter R, Oppermann M, Huang Y, Mizel D, Briggs JP, Schnermann J. Regulation of renin secretion and expression in mice deficient in beta1- and beta2-adrenergic receptors. Hypertension. 2007;50:103–9.PubMedCrossRef
62.
Golin R, Pieruzzi F, Munforti C, Busca G, Di Blasio A, Zanchetti A. Role of the renal nerves in the control of renin synthesis during different sodium intakes in the rat. J Hypertens. 2001;19:1271–7.PubMedCrossRef
63.
Holmer S, Rinne B, Eckardt KU, Le Hir M, Schricker K, Kaissling B, Riegger G, Kurtz A. Role of renal nerves for the expression of renin in adult rat kidney. Am J Physiol. 1994;266:F738–45.PubMed
64.
Kim SM, Huang Y, Qin Y, Mizel D, Schnermann J, Briggs JP. Persistence of circadian variation in arterial blood pressure in beta1/beta2-adrenergic receptor-deficient mice. Am J Physiol Regul Integr Comp Physiol. 2008;294:R1427–34.PubMedCrossRef
65.
Kim SM, Mizel D, Huang YG, Briggs JP, Schnermann J. Adenosine as a mediator of macula densa-dependent inhibition of renin secretion. Am J Physiol Renal Physiol. 2006;290:F1016–23.PubMedCrossRef
66.
Hackenthal E, Paul M, Ganten D, Taugner R. Morphology, physiology, and molecular biology of renin secretion. Physiol Rev. 1990;70:1067–116.PubMed
67.
Ichihara A, Suzuki H, Murakami M, Naitoh M, Matsumoto A, Saruta T. Interactions between angiotensin II and norepinephrine on renin release by juxtaglomerular cells. Eur J Endocrinol. 1995;133:569–77.PubMedCrossRef
68.
Kurtz A, Della Bruna R, Scholz H, Baier W. Amiloride enhances the secretion but not the synthesis of renin in renal juxtaglomerular cells. Pflugers Arch. 1991;419:32–7.PubMedCrossRef
69.
Hashimoto T, Kihara M, Sato K, Matsushita K, Tanimoto K, Toya Y, Fukamizu A, Umemura S. Expression of cyclooxygenase-2 in the juxtaglomerular apparatus of angiotensinogen gene-knockout mice. Nephron Physiol. 2006;102:p1–8.PubMedCrossRef
70.
Wolf K, Castrop H, Hartner A, Goppelt-Strube M, Hilgers KF, Kurtz A. Inhibition of the renin–angiotensin system upregulates cyclooxygenase-2 expression in the macula densa. Hypertension. 1999;34:503–7.PubMed
71.
Kihara M, Umemura S, Kadota T, Yabana M, Tamura K, Nyuui N, et al. The neuronal isoform of constitutive nitric oxide synthase is up-regulated in the macula densa of angiotensinogen gene-knockout mice. Lab Invest. 1997;76:285–94.PubMed
72.
Kihara M, Umemura S, Sugaya T, Toya Y, Yabana M, Kobayashi S, et al. Expression of neuronal type nitric oxide synthase and renin in the juxtaglomerular apparatus of angiotensin type-1a receptor gene-knockout mice. Kidney Int. 1998;53:1585–93.PubMedCrossRef
73.
Cheng HF, Wang JL, Zhang MZ, McKanna JA, Harris RC. Nitric oxide regulates renal cortical cyclooxygenase-2 expression. Am J Physiol Renal Physiol. 2000;279:F122–9.PubMed
Metadata
Title
Convergence of major physiological stimuli for renin release on the Gs-alpha/cyclic adenosine monophosphate signaling pathway
Authors
Soo Mi Kim
Josephine P. Briggs
Jurgen Schnermann
Publication date
01-02-2012
Publisher
Springer Japan
Published in
Clinical and Experimental Nephrology / Issue 1/2012
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-011-0494-1

Other articles of this Issue 1/2012

Clinical and Experimental Nephrology 1/2012 Go to the issue

Review Article

Claudins and renal salt transport

Review article

Recent advances in renal urate transport: characterization of candidate transporters indicated by genome-wide association studies

Preface

List of Contributors

Review Article

Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs

Review Article

Effects of cytokines on potassium channels in renal tubular epithelia

Review Article

Serum- and glucocorticoid-inducible kinase 1 in the regulation of renal and extrarenal potassium transport
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits