Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP141) Angiotensin II type-2 (AT2) receptor blockade in experimental radiation nephropathy.

Cohen, Eric1, Fish, Brian2, Moulder, John*,2, 1 Medicine, Milwaukee, WI, USA2 Radiation Oncology, Milwaukee, WI, USA

ABSTRACT- In a rat model, and in the clinic, blockade of angiotensin II type-1 (AT1) receptors diminishes the functional changes that occur after kidney irradiation. It has been hypothesized that some of the beneficial effects of AT1 blockade in renal disease are caused by a rise in angiotensin II that stimulates angiotensin II type-2 (AT2) receptors. If this hypothesis applies to radiation nephropathy, then blockade of AT2 receptors should exacerbate radiation nephropathy and/or counteract the beneficial effects of AT1 blockade. To assess this hypothesis, rats were given TBI plus bone marrow transplantation and then treated for 12 weeks with an AT1 blocker (L158,809), an AT2 blocker (PD123319), both blockers, or no blockers. The blockers were assessed in both mitigation regimens (where drug therapy started after irradiation but before radiation nephropathy was clinically evident) and in a treatment regimen (where drug therapy did not start until radiation nephropathy was clinically evident). The AT2 blocker alone produced a delay in the development of radiation nephropathy in both the mitigation and the treatment protocols. In the mitigation protocols, the AT2 blocker substantially enhanced the efficacy of the AT1 blocker; but in the treatment regimen combining the two blockers produced no added benefit. Studies with renal microsomes show that despite the efficacy of the AT2 blocker, we cannot detect AT2 receptors in the adult rat kidney. This implies that while both AT1 and AT2 blockers have a role to play in the mitigation and treatment of radiation nephropathy, the exact role played by the AT2 blocker is unclear. Supported by NCI grant CA24652.

Key words: nephropathy, angiotensin, receptor

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2005 RRS