Autocoids in Hypertension: Pathogenesis and End Organ Damage

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DESCRIPTION (provided by applicant): This PPG was started in September, 1982. The central theme is "the study ofthe role of vasoactive systems (autocrine, juxtacrine, paracrine and endocrine) in the regulation of renal function and blood pressure (BP) and mediation of end organ damage (EOD)". The general hypothesis to be tested is that there is a balance between systems that promote water and sodium retention, hypertension and EOD, including Angiotensin II (Ang II), prostanoids, reactive oxygen species and inflammation, and systems that antagonize these effects like Ac-SDKP, activation of the Ang II type 2 receptor (AT2), kinins, NO, PGE2/EP4, and the newly discovered cross-talk between the connecting tubule and the afferent arteriole (CTGF) which may participate in both natriuresis and renal damage. Alterations of this balance in favor of the former are responsible for retention of water and sodium and development of hypertension and EOD, while alterations of this balance in favor of the latter have therapeutic effects. We will use molecular, physiological, and pharmacological approaches' to study vasoactive systems at the subcellular, cellular, and isolated organ levels in hypertension in rats and various transgenic and gene knockout mice. We will mainly use Dahl salt-sensitive rats (Dahl SS) and Ang ll-induced hypertensive rats as models. In Project I, using Dahl SS rats, we will study whether N-acetyl-seryl-aspartyl-lysyl-proline protects against EOD by decreasing adaptive immunity. In Project II we will study whether expression of cyclooxygenase-2 and generation of PGE2 via the EP4 receptor protects against EOD in Ang ll-induced hypertension. In Project III, using Dahl SS rats, we will study whether CTGF causes glomerular damage via afferent arterole dilatation and increases in capillary glomerular pressure. In Project IV, using Dahl SS rats, we will study whether a decrease in the renal thick ascending limb AT2-signaling participates in the pathogenesis of hypertension. Four cores. Administrative (A), Analytical and Morphological (B), Mutant Mouse (C), and Biostatistics (D) will support the scientific efforts of the investigators. Te PPG provides integration of our efforts, collaboration, sharing of ideas and expertise, thus accelerating acquisition of knowledge on the causes of hypertension and EOD.