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

Abstract

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. We have shown that 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 that it might also 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 non-specific. 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, a bioassay showed that the circulating levels of the AT 2 blocker were orders-of-magnitude too low to block AT 1 receptors. We conclude that the effect of AT 2 blockade in radiation nephropathy cannot be explained by binding to the AT 1 receptor, and that the efficacy of the AT 1 blockade in the same model cannot be explained by unopposed overstimulation of the AT 2 receptor.Radiation-induced chronic renal failure is well-documented in subjects undergoing total body irradiation (TBI) for hematopoietic stem cell transplants, 1,2 and in subjects receiving radiolabeled biologicals for cancer therapy. 3,4 We and others have shown the benefit of blockade of the renin-angiotensin system in experimental 5-7 and clinical 8,9 radiation nephropathy. In a rat model of radiation nephropathy, the use of angiotensin II (AII) blockade, 5,6 or reciprocally the use of AII infusion, 10 have shown that the renin-angiotensin system is particularly important between one and three months after irradiation. Further, the efficacy of an AII type-1 (AT 1 ) receptor blocker strongly suggests that the mechanism of injury is via the AT 1 receptor. 5,9 It has been suggested that the benefit of the AT 1 receptor blockade might be via over-stimulation of the unblocked angiotensin II type-2 (AT 2 ) receptor. 11 This hypothesis implied that blockade of the AT 2 receptor would negate or even reverse the effects of AT 1 blockade. Initial studies in our model have shown that AT 2 blockade has a modest, but reproducible, beneficial effect in experimental radiation nephropathy. 12,13 A similar benefit of AT 2 blockade was found by Cao et al 14 in the remnant kidney model. However, these studies could not exclude the possibility that the effects of AT 2 blockade were non-specific, possibly via binding to the AT 1 receptor. We undertook studies to confirm the efficacy of AT 2 receptor blockade in experimental radiation nephropathy, and to elucidate the pharmacologic basis for this effect.Address for correspondence: Eric P. Cohen, Department of Medicine, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Milwaukee, WI 53226, ecohen@mcw.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early ver...

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