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 #
5R01DK064324-10
Application #
8427361
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Mullins, Christopher V
Project Start
2003-04-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$330,724
Indirect Cost
$125,013
Name
University of Southern California
Department
Physiology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Buckley, Charlotte; Nelson, Robert J; Mullins, Linda J et al. (2018) Phenotypic dissection of the mouse Ren1d knockout by complementation with human renin. J Biol Chem 293:1151-1162
Riquier-Brison, Anne D M; Sipos, Arnold; Prókai, Ágnes et al. (2018) The macula densa prorenin receptor is essential in renin release and blood pressure control. Am J Physiol Renal Physiol 315:F521-F534
Gyarmati, Georgina; Kadoya, Hiroyuki; Moon, Ju-Young et al. (2018) Advances in Renal Cell Imaging. Semin Nephrol 38:52-62
Lemos, Dario R; McMurdo, Michael; Karaca, Gamze et al. (2018) Interleukin-1? Activates a MYC-Dependent Metabolic Switch in Kidney Stromal Cells Necessary for Progressive Tubulointerstitial Fibrosis. J Am Soc Nephrol 29:1690-1705
Kaverina, Natalya V; Kadoya, Hiroyuki; Eng, Diana G et al. (2017) Tracking the stochastic fate of cells of the renin lineage after podocyte depletion using multicolor reporters and intravital imaging. PLoS One 12:e0173891
Zhang, Yue; Peti-Peterdi, János; Brandes, Anna U et al. (2017) Prasugrel suppresses development of lithium-induced nephrogenic diabetes insipidus in mice. Purinergic Signal 13:239-248
Burford, James L; Gyarmati, Georgina; Shirato, Isao et al. (2017) Combined use of electron microscopy and intravital imaging captures morphological and functional features of podocyte detachment. Pflugers Arch 469:965-974
Prókai, Ágnes; Csohány, Rózsa; Sziksz, Erna et al. (2016) Calcineurin-inhibition Results in Upregulation of Local Renin and Subsequent Vascular Endothelial Growth Factor Production in Renal Collecting Ducts. Transplantation 100:325-333
Lemos, Dario R; Marsh, Graham; Huang, Angela et al. (2016) Maintenance of vascular integrity by pericytes is essential for normal kidney function. Am J Physiol Renal Physiol 311:F1230-F1242
Peti-Peterdi, János (2016) A practical new way to measure kidney fibrosis. Kidney Int 90:941-942

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