Hypertension is the major risk factor for chronic heart failure, stroke, and chronic kidney diseases. Although many think hypertension is no longer a major concern, the lifetime risk for the development of hypertension is >80% and, still only 50% of hypertensive patients attain adequate blood pressure control. The factors contributing to the development of hypertension, and the reason why blood pressure is difficult to control in elderly patients remain incompletely understood. Although it is well recognized that regardless of genetic cause of the hypertension, the development of hypertension requires the resetting of the pressure natriuresis relationship to higher pressures, the mechanisms responsible for pressure natriuresis and its resetting in hypertension remain to be determined. We reason that increased sodium (Na+) reabsorption in the renal proximal tubule via the sodium and hydrogen exchanger 3 (NHE3) due to inappropriately elevated tissue angiotensin II (ANG II) may contribute to the resetting of pressure natriuresis responses in hypertension. We have recently demonstrated that both extracellular and intracellular ANG II increases the expression and activity of NHE3 in proximal tubule cells in vitro and in the proximal tubule of rats and mice via AT1a receptors. Further, we have generated exciting preliminary data that proximal tubule-selective deletion of NHE3 markedly attenuates pressure natriuresis and blood pressure responses in ANG II-induced hypertension. Using innovative molecular, genomic and pharmacological approaches, this proposal will test the hypothesis that NHE3 in the proximal tubule plays a critical role in mediating pressure natriuresis and that proximal tubule-selective deletion of NHE3 prevents the resetting pressure natriuresis and attenuate the development of ANG II-induced hypertension.
Three specific aims are designed to test this hypothesis.
In Specific Aim 1, we will determine whether the overexpression of NHE3 selectively in the proximal tubule will stimulate proximal tubule Na+ reabsorption, reset pressure natriuresis, and promote the development of salt- sensitive hypertension, whereas deletion of NHE3 will inhibit proximal tubule Na+ reabsorption, blunt pressure natriuresis and decrease basal blood pressure using proximal tubule-specific NHE3-KO mice, tgNhe3-/-and SGLT2-Cre+Nhe3flox/flox.
In Specific Aim 2, we will determine whether infusion of a subpressor dose of ANG II plus a high salt diet will stimulate proximal tubule Na+ reabsorption, resets pressure natriuresis, and induces hypertension by increasing the expression of NHE3 in the proximal tubule, whereas deletion of NHE3 will attenuate ANG II-induced hypertension using tgNhe3-/-and SGLT2-Cre+Nhe3flox/flox mice.
In Specific Aim 3, we will test the therapeutic efficacy of molecular knockdown of the expression of NHE3 in the proximal tubule or pharmacological inhibition of NHE3 in a subpressor ANG II-induced hypertension model. The new knowledge generated by this project will help us better understand the renal mechanisms of hypertension and develop new NHE3 inhibitors to treat elderly patients with poorly-controlled hypertension.

Public Health Relevance

Hypertension is the major risk factor for chronic heart failure, stroke, and chronic kidney diseases. Using innovative molecular, genomic, and pharmacological approaches, this project will determine the role of NHE3 in the proximal tubule in resetting the pressure natriuresis responses in hypertension. This new knowledge will lead to better understanding of the role of the kidney in ANG II-induced hypertension, and the development of new diuretic drugs to treat poorly controlled hypertension.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Ketchum, Christian J
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University of Mississippi Medical Center
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Zhuo, Jia L; Li, Xiao C (2018) De Novo DNA (de)Methylation in the Kidney. Hypertension 72:1084-1086
Li, Xiao C; Soleimani, Manoocher; Zhu, Dongmin et al. (2018) Proximal Tubule-Specific Deletion of the NHE3 (Na+/H+ Exchanger 3) Promotes the Pressure-Natriuresis Response and Lowers Blood Pressure in Mice. Hypertension 72:1328-1336
Li, Xiao C; Zhu, Dongmin; Zheng, Xiaowen et al. (2018) Intratubular and intracellular renin-angiotensin system in the kidney: a unifying perspective in blood pressure control. Clin Sci (Lond) 132:1383-1401
Li, Xiao C; Zhang, Jianfeng; Zhuo, Jia L (2017) The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res 125:21-38
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Li, Xiao C; Zhuo, Jia L (2016) Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension. Curr Hypertens Rep 18:63
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Li, Xiao C; Shull, Gary E; Miguel-Qin, Elisa et al. (2015) Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines. Physiol Rep 3:

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