OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION

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DESCRIPTION (provided by applicant): Accumulation of reactive oxygen species (ROS), notably superoxide anion (O2-) in blood vessels increases their reactivity and tone in hypertension. However, the kidney is acknowledged to play 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, an increased release of hormones such as renin, and an increased reabsorption of NaCI by the tubules which impairs the rapid and quantitative elimination of salt that underlies salt sensitivity. Since presently less is known concerning the roles of ROS in renal mechanism of hypertension, this is the focus for this proposal. We have assembled an interactive group of integrative, microvascular and micropuncture physiologists and molecular and cellular biologist to tackle this problem. Project 1 will investigate the role of O2- and specifically p22phox activation of NADPH oxidase in the kidney, in afferent arteriolar reactivity, salt excretion during salt loading and hypertension. Project 2 will investigate the causes and consequences of ROS-induced alterations in the manner in which Na+ is reabsorbed by the proximal nephron that contribute to an inefficient use of O2 for chemical work in the kidney, manifest as renal cortical hypoxia. Project 3 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/FGF-2. Project 4 will investigate the molecular mechanisms of defense against oxidative stress in the proximal tubule that are coordinated by the dopamine D5 receptor. These are supported by an Administrative, Animal and Molecular Biology Core. The goal of this work is to provide a basis for better understanding of the role of ROS in hypertension and its consequences and thereby providing a rational basis for new forms of prevention or treatment.