Role of the angiotensin II type-2 receptor in radiation nephropathy.
Experimental studies have shown that blockade of the angiotensin II type-1 (AT(1)) receptor is effective in the mitigation and treatment of radiation-induced chronic renal failure. Also, blockade of the angiotensin II type-2 (AT(2)) receptor with PD-123319 also had a modest, but reproducible, beneficial effect in experimental radiation nephropathy, and it might augment the efficacy of an AT(1) blocker (L-158,809). Those studies could not exclude the possibility that the effects of AT(2) blockade were nonspecific. The current studies confirm the efficacy of AT(2) blockade for mitigation of experimental radiation nephropathy but paradoxically find no detectable level of AT(2) receptor binding in renal membranes. However, the results of a bioassay showed that the circulating levels of the AT(2) blocker were orders-of-magnitude too low to block AT(1) receptors. The effect of AT(2) blockade in radiation nephropathy cannot be explained by binding to the AT(1) receptor, and the efficacy of the AT(1) blockade in the same model cannot be explained by unopposed overstimulation of the AT(2) receptor.
Cohen
Eric P
EP
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA. ecohen@mcw.edu
Fish
Brian L
BL
Sharma
Mukut
M
Li
X Allen
XA
Moulder
John E
JE
D000804:Angiotensin II / Q000037:antagonists & inhibitors; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D002460:Cell Line; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007674:Kidney Diseases / Q000188:drug therapy*; D008297:Male; D051379:Mice; D011725:Pyridines / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors
D057912:Angiotensin II Type 2 Receptor Blockers; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; C070967:L 158809