Hypertension occurs in nearly one out of every three US adults and is a major risk factor for stroke, heart attack, and heart failure. The molecular pathogenesis of hypertension is not well understood;however, recent findings from genetic disorders affecting blood pressure highlight the important roles of the thiazide- sensitive Na-CI cotransporter NCC and the WNK protein kinases in the distal tubule of the kidney in blood pressure regulation. Intriguingly, Na and Ca transport pathways in the distal tubule are inversely related;therefore, an increase in Ca transport in the distal tubule decreases the Na transport and in turn lowers the blood pressure. Hence, a detailed understanding of the interplay between the Na and Ca transport pathways is important in blood pressure regulation. As a gatekeeper for Ca reabsorption, TRPV5 is prominently localized in the apical membrane of the late segment of the distal convoluted tubule, where NCC and WNK4 are also expressed. WNK4 enhances TRPVS-mediated Ca transport in striking contrast to its inhibitory effect on NCC. Furthermore, the enhancing effect of WNK4 on TRPV5 is dose-dependently blocked by NCC. In addition, the enhancing effect of WNK4 on TRPV5 is abolished by chelating intracellular Ca. Based on these findings we hypothesize that WNK4 integrally regulates Na and Ca transport pathways by enhancing TRPV5 and suppressing NCC;the actions of WNK4 are also modulated by TRPV5 and NCC. We plan to test our hypothesis by pursuing three specific aims: 1) determine the mechanism by which WNK4 enhances TRPVS-mediated Ca transport;2) determine the mechanism by which NCC modulates the action of WNK4;and 3) determine the role of Ca/calmodulin in modulating WNK4-mediated regulation. The studies will be carried out using molecular, biochemical and physiological approaches with both X. laevis oocytes and MDCK strain I cells. Stable MDCK I cell lines will be developed to assess the physiological significance of the regulation mechanisms. It is expected that new insights into the regulation of Ca and Na transport pathways through the interplay between the transport proteins and their common regulator WNK4 will be obtained at the completion of the project. With new knowledge acquired from the proposed studies, it is likely a new strategy via integral regulation of Na and Ca pathways in the distal tubule could be developed for blood pressure control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK072154-04
Application #
7775096
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Ketchum, Christian J
Project Start
2007-03-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$259,553
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Wang, Lingyun; Holmes, Ross P; Peng, Ji-Bin (2017) The L530R variation associated with recurrent kidney stones impairs the structure and function of TRPV5. Biochem Biophys Res Commun 492:362-367
Wang, Lingyun; Peng, Ji-Bin (2017) Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study. Protein Sci 26:163-173
Wang, Lingyun; Holmes, Ross P; Peng, Ji-Bin (2016) Molecular Modeling of the Structural and Dynamical Changes in Calcium Channel TRPV5 Induced by the African-Specific A563T Variation. Biochemistry 55:1254-64
Na, Tao; Peng, Ji-Bin (2014) TRPV5: a Ca(2+) channel for the fine-tuning of Ca(2+) reabsorption. Handb Exp Pharmacol 222:321-57
Wu, Guojin; Peng, Ji-Bin (2013) Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. FEBS Lett 587:1717-22
Na, Tao; Wu, Guojin; Zhang, Wei et al. (2013) Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites. Am J Physiol Renal Physiol 304:F8-F18
Zhang, Yanqing; Zhang, Yuan; Bone, Robert N et al. (2012) Regeneration of pancreatic non-? endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin. PLoS One 7:e36675
Na, Tao; Wu, Guojin; Peng, Ji-Bin (2012) Disease-causing mutations in the acidic motif of WNK4 impair the sensitivity of WNK4 kinase to calcium ions. Biochem Biophys Res Commun 419:293-8
Bone, Robert N; Icyuz, Mert; Zhang, Yanqing et al. (2012) Gene transfer of active Akt1 by an infectivity-enhanced adenovirus impacts ?-cell survival and proliferation differentially in vitro and in vivo. Islets 4:366-78
Wu, Guojin; Zhang, Wei; Na, Tao et al. (2012) Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease. Am J Physiol Cell Physiol 302:C1479-91

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