Impact of angiotensin II type 2 receptor blockade on experimental radiation nephropathy.
In the rat, blockade of angiotensin II type 1 receptors diminishes the functional changes that occur after kidney irradiation. It has been hypothesized that some of the beneficial effects of angiotensin II type 1 blockers in renal disease are caused by a rise in angiotensin II that stimulates the angiotensin II type 2 receptor. If this hypothesis applied in this model, blockade of the type 2 receptor should exacerbate radiation nephropathy and/or counteract the beneficial effects of type 1 receptor blockade. To assess this hypothesis, rats were given total-body irradiation plus bone marrow transplantation and then treated for 12 weeks with a type 1 receptor blocker (L158,809), a type 2 blocker (PD123319), both blockers, or no blockers. Rats were assessed for renal function (proteinuria, hypertension, azotemia) and renal failure for up to 62 weeks. Contrary to the hypothesis, the type 2 blocker alone produced a temporary delay in the development of radiation nephropathy, and it substantially enhanced the efficacy of the type 1 blocker. This implies that both type 1 and type 2 angiotensin receptors need to be blocked to achieve the maximum level of prophylaxis of radiation nephropathy. We speculate that the beneficial effect of the angiotensin II type 2 receptor blocker is due to a reduction in radiation-induced renal cell proliferation or fibrosis.
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. jmoulder@mcw.edu
John E
JE
Moulder
Brian L
BL
Fish
Eric P
EP
Cohen
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007093:Imidazoles / Q000008:administration & dosage; D007674:Kidney Diseases / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D007677:Kidney Function Tests; D008297:Male; D011725:Pyridines / Q000008:administration & dosage; D011833:Radiation Injuries, Experimental / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism* / Q000517:prevention & control; D011835:Radiation Protection / Q000379:methods; D011836:Radiation Tolerance / Q000187:drug effects; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage; D016896:Treatment Outcome
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; C073402:PD 123319; C070967:L 158809