Renin is the rate-limiting enzymatic step in angiotensin II formation. cAMP stimulates renin release from juxtaglomerular (JG) cells. Calcium (Ca) is inhibitory, as increased extracellular Ca suppresses renin release, presumably by increasing intracellular Ca. We found that JG cells express Ca-sensing receptors (CaSR). Further, we found CaSR activation reduces basal cAMP production and renin release. Our data suggest CaSR activation increases intracellular Ca, suppressing the Ca-inhibitable isoform (V) of adenylyl cyclase in the JG cells, decreasing cAMP and inhibiting renin release. Conversely, decreased extracellular Ca should inactivate CaSR, increasing cAMP formation and thus stimulating renin release. In addition, cAMP is degraded by phosphodiesterases (PDE), and isoform PDE 1 is Ca dependent, suggesting CaSR activation exaggerates cAMP degradation, reducing renin release. We hypothesize that increased extracellular Ca activates CaSR on JG cells, thereby increasing intracellular Ca. This, in turn, reduces cAMP production by the Ca-inhibitable isoform adenylyl cyclase V and augments cAMP degradation by the Ca-dependent PDE 1, thereby reducing renin release. This hypothesis will be tested in 4 aims.
Aim I. Hypothesis: Activation of CaSR by physiological increases in extracellular Ca increases intracellular Ca and thus inhibits renin release.
Aim II. Hypothesis: Activation of CaSR inhibits renin release by activating L-type Ca channels and stimulating Ca release from intracellular stores.
Aim III. Activation of CaSR inhibits adenylyl cyclase V and activates PDE 1, both resulting in decreased cAMP and inhibition of renin release.
Aim I V. Hypothesis: Increases in delivery of NaCI to the thick ascending limb will increase interstitial Ca in the renal cortex, activating CaSR on JG cells, which will in turn suppress renin. We will activate or inhibit JG cell CaSR in culture and study changes in intracellular Ca, Ca channels, cAMP synthesis and degradation, and renin release. In vivo, we will study acute and chronic changes in cortical interstitial Ca, CaSR activation or inhibition, cAMP formation and renin secretion. This project relates to the central theme because the renin- angiotensin system is a renal paracrine/autocrine system influencing renal perfusion, Na, Ca and blood pressure. The information from this project will be integrated with that from all other projects. It will use all of the cores. Our findings may lead to new treatments of hypertension from new insights into mechanisms that regulate renin.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL090550-05
Application #
8448092
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$356,703
Indirect Cost
$113,220
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Gordish, Kevin L; Beierwaltes, William H (2014) Resveratrol induces acute endothelium-dependent renal vasodilation mediated through nitric oxide and reactive oxygen species scavenging. Am J Physiol Renal Physiol 306:F542-50
Ortiz-Capisano, M Cecilia; Reddy, Mahendranath; Mendez, Mariela et al. (2013) Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP(3) pathway and the ryanodine receptor. Am J Physiol Renal Physiol 304:F248-56
Atchison, Douglas K; Beierwaltes, William H (2013) The influence of extracellular and intracellular calcium on the secretion of renin. Pflugers Arch 465:59-69
Ortiz-Capisano, M Cecilia; Atchison, Douglas K; Harding, Pamela et al. (2013) Adenosine inhibits renin release from juxtaglomerular cells via an A1 receptor-TRPC-mediated pathway. Am J Physiol Renal Physiol 305:F1209-19
Ramseyer, Vanesa D; Garvin, Jeffrey L (2013) Tumor necrosis factor-ýý: regulation of renal function and blood pressure. Am J Physiol Renal Physiol 304:F1231-42
Beierwaltes, William H (2013) Endothelial dysfunction in the outer medullary vasa recta as a key to contrast media-induced nephropathy. Am J Physiol Renal Physiol 304:F31-2
Atchison, Douglas K; Harding, Pamela; Beierwaltes, William H (2013) Vitamin D increases plasma renin activity independently of plasma Ca2+ via hypovolemia and *-adrenergic activity. Am J Physiol Renal Physiol 305:F1109-17
Cabral, Pablo D; Garvin, Jeffrey L (2013) Less potassium coming out, less sodium going in: phenotyping ROMK knockout rats. Hypertension 62:240-1
Ren, Yilin; D'Ambrosio, Martin A; Wang, Hong et al. (2012) Mechanisms of carbon monoxide attenuation of tubuloglomerular feedback. Hypertension 59:1139-44
Beierwaltes, William H (2012) Are microRNAs the key to transforming renin progenitor cells in the afferent renal circulation? Am J Physiol Renal Physiol 302:F27-8

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