Role of Thick Ascending Limb Free Radicals in Angiotensin II-Dependent Hyperten

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Principal Investigator/Program Director (Last, First, Middle): Garvin, Jeffrey L, Ph.D./CaiTeterO, Oscar A., M.D. PROJECT V Role of Thick Ascending Limb Free Radicals in Angiotensin ll-lnduced Hypertension Project Investigator: Jeffrey L. Garvin, Ph.D. Co-Investigator: Pablo A. Ortiz, Ph.D. Co-Investigator: Patrick J. Pagano, Ph.D. Co-Investigator: Xiao-Ping Yang, M.D. Abstract There is a balance between factors promoting renal salt and water excretion [i.e., nitric oxide (NO)] and those favoring retention [i.e., superoxide (O2")]. In angiotensin II (Ang Independent hypertension and other forms, this balance favors the latter. Inappropriate salt retention by the kidney may lead or contribute to Ang II- dependent hypertension. The thick ascending limb absorbs 20-30% of the filtered NaCI load. We have shown that NO specifically produced by endothelial or type 3 NO synthase (eNOS) in the thick ascending limb acts as an autacoid, inhibiting NaCI absorption, and may thereby contribute significantly to salt and water excretion. We have also shown that O2" stimulates NaCI absorption in the thick ascending limb. Ang ll-induced hypertension caused by infusion of low to moderate doses of Ang II is dependent on salt intake. These data indicate a significant role of the kidney in this form of hypertension. During Ang ll-induced hypertension renal cortical eNOS expression is enhanced, but our data show that medullary thick ascending limb expression decreases. In contrast, production of reactive oxygen species (including O2") is elevated in both regions. Currently, it is unclear how Ang ll-induced hypertension affects net NaCI absorption by the medullary thick ascending limb, or whether these effects are mediated by changes in NO and O2~ production. Thus we hypothesize that during Ang ll-induced hypertension there is a shift in the balance between the natriuretic factor NOand the antinatriuretic factor O2'in the thick ascending limb that favors the latter and enhances salt absorption. Aim I. Hypothesis: Ang ll-induced hypertension diminishes NOproduction in the thick ascending limb in part by reducing eNOS expression via release of tumor necrosis factor a (TNF a). Aim II. Hypothesis: Agonist-induced eNOS activation is reduced in Ang ll-induced hypertension due to increased phosphorylation at the inhibitory