It is well known that aldosterone affects ENaC activity in the distal nephron to regulate sodium balance and, consequently blood pressure. This proposal challenges our current view on how ENaC activity responds to variations in dietary salt intake by identifying aldosterone-independent means of this regulation. Specifically, we have developed evidence that coordinated coupling between stimulatory Ang II and inhibitory Bradykinin (BK) cascades is necessary for proper adaptation of ENaC activity to variations in dietary sodium. Our preliminary work strongly supports our central hypothesis that Ang II directly stimulates ENaC-mediated Na+- reabsorption in the mammalian aldosterone-sensitive distal nephron (ASDN) and this regulation is non- redundant to aldosterone actions on ENaC. In addition, we hypothesize that the activation of Ang II cascade during sodium restriction further augments ENaC activity by limiting inhibitory actions of BK signaling on ENaC. In contrast, BK signaling is necessary to suppress ENaC activity during elevated salt intake with its dysfunction in mice lacking B2 receptors causing excessive Na+ conservation as a result of elevated ENaC activity. Importantly, mice with deleted B2 receptors develop salt-sensitive hypertension. To test this hypothesis we address 3 specific aims: 1) Establish the physiological importance of aldosterone-independent regulation of ENaC by systemic salt intake. Define the role of Ang II regulation of ENaC in this process. 2) Define the mechanism of action and delineate the cellular signaling pathway of Ang II regulation of ENaC activity in mammalian ASDN. 3) Determine how functional coupling between Ang II and BK signaling cascades controls ENaC activity in response to changes in systemic salt and establish the patho-physiological consequences of disrupting this regulation in B2 -/- mice. Our experimental approach ranges from electrophysiology in native distal nephron cells to whole animal balance studies and will combine 1) patch clamp measurements of ENaC activity in the split-open murine distal nephrons with ENaC expression levels probed by western blotting/RPPA and immunohistochemistry, and 2) balance studies to assess renal Na+ excretion with molecular genetic tools in mice to define a physiological role of aldosterone-independent regulation of ENaC and sodium handling by the kidney. From a pharmacological standpoint, the importance of this work will urge the development of B2 agonists as tools for correction of sodium handling in the distal nephron to control blood pressure.

Public Health Relevance

The problem of high blood pressure is particularly important since more than 20% of all Americans suffer from high blood pressure. Appropriate salt handling by the kidneys is pivotal to blood pressure control. This proposal identifies new signaling cascade that is important for regulation of sodium handling in the distal nephron by dietary salt intake.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK095029-02
Application #
8540426
Study Section
Special Emphasis Panel (ZRG1-DKUS-E (03))
Program Officer
Ketchum, Christian J
Project Start
2012-09-05
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$319,030
Indirect Cost
$109,142
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Mamenko, Mykola; Dhande, Isha; Tomilin, Viktor et al. (2016) Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus. J Am Soc Nephrol 27:2035-48
Tomilin, Viktor; Mamenko, Mykola; Zaika, Oleg et al. (2016) Role of renal TRP channels in physiology and pathology. Semin Immunopathol 38:371-83
Zaika, Oleg; Tomilin, Viktor; Mamenko, Mykola et al. (2016) New perspective of ClC-Kb/2 Cl- channel physiology in the distal renal tubule. Am J Physiol Renal Physiol 310:F923-30
Hoover, Robert S; Tomilin, Viktor; Hanson, Lauren et al. (2016) PTH modulation of NCC activity regulates TRPV5 Ca2+ reabsorption. Am J Physiol Renal Physiol 310:F144-51
Zaika, Oleg; Palygin, Oleg; Tomilin, Viktor et al. (2016) Insulin and IGF-1 activate Kir4.1/5.1 channels in cortical collecting duct principal cells to control basolateral membrane voltage. Am J Physiol Renal Physiol 310:F311-21
Mamenko, M; Zaika, O; Boukelmoune, N et al. (2015) Deciphering physiological role of the mechanosensitive TRPV4 channel in the distal nephron. Am J Physiol Renal Physiol 308:F275-86
Mamenko, Mykola; Zaika, Oleg; Boukelmoune, Nabila et al. (2015) Control of ENaC-mediated sodium reabsorption in the distal nephron by Bradykinin. Vitam Horm 98:137-54
Pavlov, Tengis S; Ilatovskaya, Daria V; Palygin, Oleg et al. (2015) Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium. J Vis Exp :
Zaika, Oleg; Mamenko, Mykola; Boukelmoune, Nabila et al. (2015) IGF-1 and insulin exert opposite actions on ClC-K2 activity in the cortical collecting ducts. Am J Physiol Renal Physiol 308:F39-48
Mamenko, Mykola; Zaika, Oleg; Pochynyuk, Oleh (2014) Direct regulation of ENaC by bradykinin in the distal nephron. Implications for renal sodium handling. Curr Opin Nephrol Hypertens 23:122-9

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