Diabetes and hypertension are two major risk factors for chronic kidney disease. Inappropriate activation of the intrarenal renin-angiotensin system (the hormone system that regulates blood pressure and water balance, RAS) substantially increases risk and progression to renal injury. Current treatments targeting the RAS only slow, rather than halt the progression to chronic kidney disease. Therefore, we urgently need to understand the mechanisms which activate this system and lead to increased blood pressure and renal injury in order to develop new therapeutic targets to control the progression to end-stage organ damage. Our long- term goal is to define the contributions of the newly discovered prorenin receptor in the collecting duct to the pathogenesis of hypertension and renal injury and to introduce a paradigm-challenging concept which explains the interaction between the prorenin receptor and prorenin in the collecting duct which highlights the functional roles of this interaction in the regulation of sodium reabsorption, blood pressure, and development and progression of renal fibrosis in diabetes mellitus and hypertension. Our central hypothesis is that during hypertension and hyperglycemia, the interaction between the prorenin receptor and prorenin in the collecting duct contribute to increased blood pressure and to the development and progression to renal injury by mechanisms that are both dependent and independent of angiotensin II, the major effector hormone of the renin-angiotensin system. This hypothesis will be tested addressing the following specific aims: (1) Demonstrate that the prorenin receptor is required for the activation of prorenin produced in the collecting ducts; (2) Determine the functional consequences of the interaction between prorenin and soluble prorenin receptor in the collecting duct during angiotensin II-dependent hypertension; and (3) Demonstrate that prorenin-dependent activation of membrane bound prorenin receptor to collecting duct cells leads to renal fibrosis during Streptozotocin-induced hyperglycemia. We will attain these specific aims using a vertical and innovated approach which will include in vivo and in vitro experiments using a unique mouse model developed by our laboratory with a specific genetic deletion of the prorenin receptor in the collecting duct. Experiments will be assessed using integrated physiological, molecular and histological methodologies. The successful completion of the research proposed is of great significance because findings will provide definitive in vivo evidence of the functional role of the prorenin receptor in the collecting duct, which will providea rationale for the generation of novel drugs targeting this receptor. Understanding the mechanism of this novel pathway will be of relevance to public health because it will allow the optimization of treatment in conditions associated with augmented prorenin receptor-prorenin interaction such as hypertension, diabetes, and preeclampsia.

Public Health Relevance

The proposed research is relevant to public health because a better understanding of the functional roles of the novel discovered, prorenin receptor, in the regulation of salt absorption by the kidney and the development of kidney damage in diabetes and hypertension (high blood pressure) will provide solid bases for new therapeutic applications of current available drugs that directly inhibit the enzyme renin and for the development of novel drugs targeting the prorenin receptor. Moreover, the proposed studies are relevant to NIH's mission since progress on treatment of kidney damage will help reduce the burdens of patients with cardiovascular diseases, such as hypertension and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK104375-05
Application #
9526476
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Ketchum, Christian J
Project Start
2014-09-22
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Tulane University
Department
Physiology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Cortes, Aline L; Gonsalez, Sabrina R; Rioja, Lilimar S et al. (2018) Protective outcomes of low-dose doxycycline on renal function of Wistar rats subjected to acute ischemia/reperfusion injury. Biochim Biophys Acta Mol Basis Dis 1864:102-114
Salinas-Parra, Nicolás; Reyes-Martínez, Cristian; Prieto, Minolfa C et al. (2017) Prostaglandin E2 Induces Prorenin-Dependent Activation of (Pro)renin Receptor and Upregulation of Cyclooxygenase-2 in Collecting Duct Cells. Am J Med Sci 354:310-318
Gonzalez, Alexis A; Zamora, Leonardo; Reyes-Martinez, Cristian et al. (2017) (Pro)renin receptor activation increases profibrotic markers and fibroblast-like phenotype through MAPK-dependent ROS formation in mouse renal collecting duct cells. Clin Exp Pharmacol Physiol 44:1134-1144
Gonzalez, Alexis A; Cifuentes-Araneda, Flavia; Ibaceta-Gonzalez, Cristobal et al. (2016) Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct. Am J Physiol Renal Physiol 310:F284-93
Shao, Weijian; Miyata, Kayoko; Katsurada, Akemi et al. (2016) Increased angiotensinogen expression, urinary angiotensinogen excretion, and tissue injury in nonclipped kidneys of two-kidney, one-clip hypertensive rats. Am J Physiol Renal Physiol 311:F278-90
Gonzalez, Alexis A; Liu, Liu; Lara, Lucienne S et al. (2015) PKC-?-dependent augmentation of cAMP and CREB phosphorylation mediates the angiotensin II stimulation of renin in the collecting duct. Am J Physiol Renal Physiol 309:F880-8
Gonzalez, Alexis A; Prieto, Minolfa C (2015) Roles of collecting duct renin and (pro)renin receptor in hypertension: mini review. Ther Adv Cardiovasc Dis 9:191-200
Gonzalez, Alexis A; Prieto, Minolfa C (2015) Renin and the (pro)renin receptor in the renal collecting duct: Role in the pathogenesis of hypertension. Clin Exp Pharmacol Physiol 42:14-21
Majid, Dewan S A; Prieto, Minolfa C; Navar, Luis Gabriel (2015) Salt-Sensitive Hypertension: Perspectives on Intrarenal Mechanisms. Curr Hypertens Rev 11:38-48
Cuevas, Catherina A; Gonzalez, Alexis A; Inestrosa, Nibaldo C et al. (2015) Angiotensin II increases fibronectin and collagen I through the ?-catenin-dependent signaling in mouse collecting duct cells. Am J Physiol Renal Physiol 308:F358-65