The renin-angiotensin system (RAS) is one of the most important regulatory mechanisms of body fluid and electrolyte homeostasis and blood pressure maintenance. The juxtaglomerular apparatus (JGA) is a key anatomical site of RAS where renin, the rate-limiting step of RAS, and its precursor prorenin are synthesized and released in a highly regulated fashion. One of the recent exciting topics in RAS research is the discovery of the (pro)renin receptor [(P)RR] challenging the existing simplistic RAS model (angiotensinogen, renin, converting enzyme, angiotensin (Ang) peptides and receptors). (Pro)renin binding by the receptor not only causes non- proteolytic activation of the enzyme and generation of AngI, but also triggers AngII-independent intracellular signaling. A functional role for prorenin was suspected long ago since elevated plasma prorenin is a well-recognized predictor of microvascular complications in cardiovascular disease and diabetes. Prorenin and its receptor have become new elements of RAS, hot players and therapeutic targets in disease. During the past grant cycle we successfully characterized important JGA functions, the tubuloglomerular feedback (TGF) and renin release mechanisms and their important constituents including the ATP and connexin-mediated calcium wave. Also, we pioneered a unique multi-photon imaging approach to directly and quantitatively visualize the intact kidney, monitor the basic parameters of kidney function in vivo including (pro)renin content, release and tissue activity. Our overall hypothesis is that the (P)RR, localized in the basolateral membrane of macula densa (MD) cells, and its downstream signaling is an important and novel modulator of MD and JGA functions. More precisely, we hypothesize that the (P)RR constitutes a short-loop positive feedback stimulating renin release from adjacent JG cells which includes activation of MD MAP kinases and the classic PGE2 synthetic and release machinery. We also hypothesize that another novel, but inhibitory JGA mechanism, a connexin and ATP-mediated vascular calcium signal helps to balance renin synthesis and release.
Aim 1 will test for the expression, regulation, and signaling of the (P)RR in macula densa cells using molecular techniques.
Aim 2 will establish the role of macula densa (P)RR in JGA function using multi-photon fluorescence imaging of the intact kidney in vivo or freshly dissected, microperfused JGA preparations in vitro and a number of transgenic approaches and animal models.
Aim 3 will identify the mechanism and importance of Cx45/ATP-mediated inhibition of renin release using multi-photon imaging. These original and novel studies are expected to provide clinically important information that can be used to develop new drugs and therapeutic approaches for the better treatment of cardiovascular and kidney diseases.

Public Health Relevance

Hypertension is a major risk factor for cardiovascular diseases, affecting about 25% of the population. The kidney is central to maintenance of normal blood pressure and to the pathogenesis of hypertension because of its dominant role in the regulation of salt and water balance. In this proposal we will directly visualize novel mechanisms in the kidney using a state-of- the-art imaging technology which will allow us to discover how the kidney operates in real time to control blood volume and pressure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064324-09
Application #
8217283
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Mullins, Christopher V
Project Start
2003-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
9
Fiscal Year
2012
Total Cost
$342,796
Indirect Cost
$129,624
Name
University of Southern California
Department
Physiology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Peti-Peterdi, János; Burford, James L; Hackl, Matthias J (2014) Can kidney regeneration be visualized? Nephron Exp Nephrol 126:86
Burford, James L; Villanueva, Karie; Lam, Lisa et al. (2014) Intravital imaging of podocyte calcium in glomerular injury and disease. J Clin Invest 124:2050-8
Peti-Peterdi, Janos (2013) Mitochondrial TCA cycle intermediates regulate body fluid and acid-base balance. J Clin Invest 123:2788-90
Gueutin, Victor; Vallet, Marion; Jayat, Maximilien et al. (2013) Renal *-intercalated cells maintain body fluid and electrolyte balance. J Clin Invest 123:4219-31
Kishore, Bellamkonda K; Zhang, Yue; Gevorgyan, Haykanush et al. (2013) Cellular localization of adenine receptors in the rat kidney and their functional significance in the inner medullary collecting duct. Am J Physiol Renal Physiol 305:F1298-305
Peti-Peterdi, János; Gevorgyan, Haykanush; Lam, Lisa et al. (2013) Metabolic control of renin secretion. Pflugers Arch 465:53-8
Chambrey, Regine; Kurth, Ingo; Peti-Peterdi, Janos et al. (2013) Renal intercalated cells are rather energized by a proton than a sodium pump. Proc Natl Acad Sci U S A 110:7928-33
Eladari, Dominique; Chambrey, Régine; Peti-Peterdi, Janos (2012) A new look at electrolyte transport in the distal tubule. Annu Rev Physiol 74:325-49
Peti-Peterdi, Janos; Burford, James L; Hackl, Matthias J (2012) The first decade of using multiphoton microscopy for high-power kidney imaging. Am J Physiol Renal Physiol 302:F227-33
Mironova, Elena; Peti-Peterdi, Janos; Bugaj, Vladislav et al. (2011) Diminished paracrine regulation of the epithelial Na+ channel by purinergic signaling in mice lacking connexin 30. J Biol Chem 286:1054-60

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