Abstract

FOR PROJECT 1 The goal of this research proposal is to extend our studies of how the renin angiotensin system (RAS) and dopaminergic systems regulate renal sodium transport and ultimately their involvement in the etiology of salt sensitivity (a pathology affecting 51% of hypertensive and 26% of normotensive individuals). Specifically, we will test the overall hypothesis that the electrogenic sodium bicarbonate cotransporters NBCe2 (coded by the gene SLC4A5) and NBCe1 (coded by the gene SLC4A4) are involved with sodium homeostasis through regulation by the RAS and dopaminergic systems and other critical sodium transporters (NHE3 and Na+,K+/ATPase). Furthermore, two single nucleotide polymorphisms (SNPs) in SLC4A5 lead to the dysregulation of sodium reabsorption through increases in SLC4A5 mRNA expression and NBCe2 activity.
The specific aims for this project are: (1) To test the hypothesis that salt sensitivity is due to aberrant dopaminergic and angiotensin regulation of renal proximal tubule sodium transport caused by intronic variants in SLC4A5 and a variant of GRK4 (GRK4-65L) and (2) To test the hypothesis in specific aim 1 by investigating the epigenetic regulation of the expression of NBCe2 (and related ion transporters) by an HNF4A binding site in the SLC4A5 gene.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL074940-15
Application #
9949770
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
OH, Youngsuk
Project Start
Project End
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
15
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904

  Publications

Muntner, Paul; Whelton, Paul K; Woodward, Mark et al. (2018) A Comparison of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline and the 2017 American Diabetes Association Diabetes and Hypertension Position Statement for U.S. Adults With Diabetes. Diabetes Care 41:2322-2329
Ye, Zhengmeng; Lu, Xi; Deng, Yi et al. (2018) In Utero Exposure to Fine Particulate Matter Causes Hypertension Due to Impaired Renal Dopamine D1 Receptor in Offspring. Cell Physiol Biochem 46:148-159
Yang, Yang; Chen, Caiyu; Fu, Chunjiang et al. (2018) Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells. J Am Soc Hypertens 12:135-145
Li, Fengmin; Yang, Jian; Villar, Van Anthony M et al. (2018) Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice. Diabetologia 61:727-737
Wang, Xiaoyan; Villar, Van Anthony; Tiu, Andrew et al. (2018) Dopamine D2 receptor upregulates leptin and IL-6 in adipocytes. J Lipid Res 59:607-614
Luo, Hao; Chen, Caiyu; Guo, Li et al. (2018) Exposure to Maternal Diabetes Mellitus Causes Renal Dopamine D1 Receptor Dysfunction and Hypertension in Adult Rat Offspring. Hypertension 72:962-970
Wu, Gengze; Jose, Pedro A; Zeng, Chunyu (2018) Noncoding RNAs in the Regulatory Network of Hypertension. Hypertension 72:1047-1059
Asico, Laureano D; Cuevas, Santiago; Ma, Xiaobo et al. (2018) Nephron segment-specific gene expression using AAV vectors. Biochem Biophys Res Commun 497:19-24
Tiu, Andrew C; Bishop, Michael D; Asico, Laureano D et al. (2017) Primary Pediatric Hypertension: Current Understanding and Emerging Concepts. Curr Hypertens Rep 19:70
Diao, Zhenyu; Asico, Laureano D; Villar, Van Anthony M et al. (2017) Increased renal oxidative stress in salt-sensitive human GRK4?486V transgenic mice. Free Radic Biol Med 106:80-90

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