Primary (essential) hypertension affects 28 % of the adult population in the United States and leads to premature cardiovascular, cerebrovascular and renal disease. The overall goal of Project #2 is to understand the interactions among the major renal Na+ regulatory pathways (dopamine 1, [DIR], dopamine 3 [DSR], and angiotensin type 1 [AT1R] receptors) which are critical to the regulation of blood pressure in humans. In experimental animals, the renal renin-angiotensin system and the renal dopaminergic system independently, and in concert, regulate renal Na+ excretion, and defects in these pathways can lead to hypertension. We have reported that the hypertension in mice overexpressing the human G protein-coupled receptor kinase type 4 variant, GRK4 A142V is associated with decreased renal D1R expression and function and increased AT1R expression and function. A similar mechanism may be operating in human essential hypertension. Expression of GRK4 variants in cell lines replicates the D1R defect noted in human renal proximal tubule cells from hypertensive subjects. Inhibition of GRK4 function or expression normalizes D1R function in human renal proximal tubule cells/cell lines expressing GRK4 variants. Moreover, renal selective prevention of the expression of GRK4 in spontaneously hypertensive rats attenuates the development of hypertension. The uncoupling of D1R in hypertension impairs the inhibitory paracrine regulation by dopamine (DA) of renal Na+ transport in the proximal tubule and even more distal nephron segments. Because DA, via D1Rs and D3Rs, normally antagonizes the increase in Na+ reabsorption caused by angiotensin II, via AT1Rs, enhanced renal Na+ reabsorption In hypertension may be due to an unopposed AT1R action (by DA). The overall hypothesis of Project #2 is that AT1R-mediated antinatriuresis is opposed by D1Rs and D3Rs, acting in concert in normal human subjects, and that this protective mechanism is deficient in patients with essential hypertension.
Three specific aims will determine the interactions among D1Rs and D3Rs and AT1Rs and their consequences in terms of Na+ excretion: (1) to test the hypothesis that D3R activation induces natriuresis, in part, by an action in the renal proximal and distal tubule in normotensive but not in hypertensive human subjects;(2) to test the hypothesis that D1Rs and D3Rs act synergistically in the induction of natriuresis in normal human subjects but not in hypertensive subjects;and (3) to test the hypothesis that antinatriuresis in human hypertension is related to AT1R-mediated Na+ reabsorption that is unopposed by DA. Hypertension is a complex polygenic disease. However, based on our findings, GRK4 regulation of a limited number of G protein-coupled receptors (GPCRs), and the downstream regulation of genes/proteins by GPCRs, e.g., D1R, D3R, and AT1R, makes a single gene, GRK4, a key contributor in the pathogenesis of essential hypertension.
These studies will provide clinical correlation with the biochemical findings of projects 1 and 3 on the genetic causes of human essential hypertension. Understanding the overall physiologic mechanisms that control blood pressure and sustain hypertension can aid in focusing research efforts into successful targeted therapeutic stratagies.
|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|
|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|
|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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