ANGIOTENSIN RECEPTOR TOPOLOGY AND FUNCTION

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DESCRIPTION (Adapted from the Applicant's Abstract): The renal proximal tubule (PT) plays an important role in homeostasis by reabsorption of salt and water and yet is often exposed to toxic and ischemic insults, and thus constantly undergoes injury and repair. Indeed, PT injury is a major cause of renal failure. PT contains a complete renin-angiotensin system (RAS) and produces endogenous angiotensin II (Ang II). Angiotensin converting enzyme inhibitor effectively slows progression of chronic renal insufficiency, and may ameliorate tubulointerstitial injury. Therefore, the RAS and its product, Ang II, may play an important role in PT injury and repair. The principal investigator proposes to use lines (that he has developed and characterized) of immortalized rat proximal tubule cells (IRPTC) from weanling rat kidney that express all the components of the RAS, including Ang II receptor subtypes AT1 and AT2, as a model. The studies will focus on the role of Ang II in PT injury and repair. The overall hypothesis is that PT injury involves modulation of both AT1 and AT2 in PT; furthermore, that AT1 receptor activation leads to cell growth and proliferation, while AT2 inhibits growth as well as AT1 expression, later leading to programmed cell death. Using an IRPTC oxidant injury model, the Specific Aims proposed will test the following hypotheses: 1) that PT injury initially upregulates both AT1 and AT2 expression; 2) that PT injury induces release of endogenous Ang II which influences subsequent transcription of both AT1 and AT2 receptors; and 3) that during repair there is crosstalk between AT2 and AT1, i.e., that AT2 receptor activation inhibits AT1 expression through intracellular Na+ loading, and later AT2 induces programmed cell death.