Role of the angiotensin II type-2 receptor in radiation nephropathy

Experimental studies have shown that blockade of the angiotensin II type-1 (AT1) receptor is effective in the mitigation and treatment of radiation-induced chronic renal failure. Also, blockade of the angiotensin II type-2 (AT2) receptor with PD-123319 also had a modest, but reproducible, beneficial effect in experimental radiation nephropathy, and it might augment the efficacy of an AT1 blocker (L-158,809). Those studies could not exclude the possibility that the effects of AT2 blockade were nonspecific. The current studies confirm the efficacy of AT2 blockade for mitigation of experimental radiation nephropathy but paradoxically find no detectable level of AT2 receptor binding in renal membranes. However, the results of a bioassay showed that the circulating levels of the AT2 blocker were orders-of-magnitude too low to block AT1 receptors. The effect of AT2 blockade in radiation nephropathy cannot be explained by binding to the AT1 receptor, and the efficacy of the AT1 blockade in the same model cannot be explained by unopposed overstimulation of the AT2 receptor.