Angiotensin Type 2 Receptor Antagonism Confers Renal Protection in a Rat Model of Progressive Renal Injury

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Abstract
The role of the angiotensin type 2 (AT2) receptor in the pathogenesis of progressive renal injury has not been previously elucidated. The renal expression of the AT1 and AT2 receptors in subtotally nephrectomized rats (STNx) and the effects of AT2 receptor blockade on renal injury were explored. Reduced renal expression of the AT1 but not the AT2 receptor was observed in STNx by reverse transcription–PCR, by in vitro autoradiography, and by immunohistochemical staining. The STNx rats were randomly assigned to AT1 receptor antagonist valsartan, AT2 receptor antagonist PD123319, or the combination of both for 4 wk. Increased proteinuria in STNx rats was reduced by PD123319 but to a lesser degree when compared with valsartan. Reduced gene and protein expression of the slit diaphragm protein nephrin was prevented by either valsartan or PD123319. Expression of osteopontin, proliferating cell nuclear antigen, and monocyte/macrophage infiltration was increased in STNx rats and was reduced by both AT1 and AT2 receptor antagonists. These effects of AT2 receptor antagonism were observed in the presence of increased BP in STNx rats. These findings suggest that blockade of the AT2 receptor alone confers a degree of renal protection; in particular, it seems that the combination of the AT1 and AT2 receptor antagonists may confer additive renal effects than either receptor antagonist as monotherapy.