Reactive oxygen species (ROS), notably superoxide anion (O2-) in blood vessels increases their reactivity and tone in hypertension. The kidney plays the predominant role in long-term BP regulation. Renal mechanisms of hypertension center on an increased reactivity or tone of the afferent arteriole which limits the transmission of pressure into the kidney and hence increases the set point of BP regulation together with increased release of renin and an increased re-absorption of NaCl by the tubules which underlies salt sensitivity. The focus of this proposal is on the roles of ROS in renal mechanism of hypertension. We have assembled an interactive group of integrative, microvascular and micropuncture physiologists and molecular and cellular biologist to tackle this problem. Project 1 will center on the role of ROS in modulating myogenic responses (MRs) of the mouse afferent arteriole. It compares responses in normal mice, where ROS generation enhanced MRs and the reduced renal mass model of chronic kidney disease and the angiotensin infusion model of hypertension where ROS impaired MRs. It combines direct measures of MR in isolated perfused afferent arterioles with gene arrays and RNA seq analyses on these microvessels and fluorescence quantitation of ROS, and Ca2+ using knockout and transgenic mice or mice with single kidney gene transfection or deletion. Project 2 will investigate a new paradigm of growth-factor related oxidative stress and hypertension using a mouse model of inducible activation of basic fibroblast growth factor and its interaction with specific FGF molecules and receptors. Studies combine BP and afferent arteriolar reactivity to angiotensin with cellular and molecular studies of the signaling mechanism and their interaction with ROS. Project 3 will investigate the molecular mechanisms of defense against oxidative stress in the proximal tubule that are coordinated by the dopamine D2 receptors. The new hypothesis is that D2-R signaling enhances paraoxygenase-2 which activates a transcriptional redox-regulating pathways initiated by DJ2 to inhibit NADPH oxidase-induced ROS. These are supported by the Administrative, Animal and Bioanalytical Cores.

Public Health Relevance

Oxidative stress accompanies hypertension, chronic kidney disease and major cardiovascular risk factors but the mechanisms that link these together in blood vessels and the kidneys are poorly understood. The goal of this work is to understand the role of oxidative stress in hypertension and its consequences and thereby to provide a rational basis for new forms of prevention or treatment. (End of Abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Georgetown University
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Pei, Lei; Solis, Glenn; Nguyen, Mien T X et al. (2016) Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. J Clin Invest 126:2509-18
Wang, Zheng; Zeng, Chunyu; Villar, Van Anthony M et al. (2016) Human GRK4γ142V Variant Promotes Angiotensin II Type I Receptor-Mediated Hypertension via Renal Histone Deacetylase Type 1 Inhibition. Hypertension 67:325-34
Jose, Pedro A; Yang, Zhiwei; Zeng, Chunyu et al. (2016) The importance of the gastrorenal axis in the control of body sodium homeostasis. Exp Physiol 101:465-70
Sanada, H; Yoneda, M; Yatabe, J et al. (2016) Common variants of the G protein-coupled receptor type 4 are associated with human essential hypertension and predict the blood pressure response to angiotensin receptor blockade. Pharmacogenomics J 16:3-9
Zhang, Gensheng; Wang, Qiaoling; Zhou, Qin et al. (2016) Protective Effect of Tempol on Acute Kidney Injury Through PI3K/Akt/Nrf2 Signaling Pathway. Kidney Blood Press Res 41:129-38
Jose, Pedro A; Felder, Robin A; Yang, Zhiwei et al. (2016) Gastrorenal Axis. Hypertension 67:1056-63
Li, Lingli; Lai, En Yin; Wellstein, Anton et al. (2016) Differential effects of superoxide and hydrogen peroxide on myogenic signaling, membrane potential, and contractions of mouse renal afferent arterioles. Am J Physiol Renal Physiol 310:F1197-205
Zhang, Yanrong; Jiang, Xiaoliang; Qin, Chuan et al. (2016) Dopamine D2 receptors' effects on renal inflammation are mediated by regulation of PP2A function. Am J Physiol Renal Physiol 310:F128-34
Konkalmatt, Prasad R; Asico, Laureano D; Zhang, Yanrong et al. (2016) Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure. JCI Insight 1:
Wang, Renjun; Huang, Qian; Zhou, Rui et al. (2016) Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus. Circ Heart Fail 9:e002261

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