Verapamil prevents the apoptotic and hemodynamic changes in response to unilateral ureteral obstruction

Abstract

Obstruction of the urinary tract has marked effects on renal blood flow, glomerular filtration rate (GFR), and tubular function. Moreover, ureteral obstruction results in an injury response that can progress to irreversible renal fibrosis and tubular atrophy by apoptosis. We examined the effect of a calcium channel blocker (verapamil) on renal functions and the abundance of apoptotic (p53, Fas, proliferating cell nuclear antigen [PCNA]) markers 1 week after Unilateral Ureteral Obstruction (UUO). Immunohistochemistry studies revealed that UUO was markedly associated with up-regulation in the expression of p53 (1550 +/- 82 vs 100 +/- 23%), Fas (657 +/- 48 vs 100 +/- 31%), and proliferating cell nuclear antigen (945 +/- 70 vs 100 +/- 17% of sham levels). Administration of verapamil normalized the up-regulation of apoptotic markers p53 (724 +/- 116 vs 1550 +/- 82%); Fas (162 +/- 38 vs 657 +/- 48%) and PCNA (353 +/- 54 vs 945 +/- 70%). Furthermore, tubular diameter, as an important marker for detecting tubular atrophy was significantly decreased compared to those in UUO rabbits. The percent area of interstitial fibrosis in UUO kidneys was significantly greater than that in Verapamil-treated kidneys. Importantly, Verapamil reduced the development of interstitial fibrosis in UUO rabbits. We measured the GFR and renal blood flow in UUO. Short-term Verapamil challenge partially prevented the decrease in GFR (non-treated UUO: 62 +/- 14; Verapamil + UUO: 119 +/- 7; Sham: 127 +/- 23 microL x min(-1) x kg body wt(-1), P < 0.05) and renal blood flow (non-treated UUO: 1.1 +/- 0.4; Verapamil + UUO: 5.0 +/- 0.2; sham: 6.3 +/- 0.2 mL x min(-1) x kg body wt(-1), P < 0.05). Verapamil significantly prevents impairment in renal function and also prevents the up-regulation of p53, Fas, and PCNA during UUO, demonstrating a marked renoprotective effect of Verapamil treatment in conditions with urinary tract obstruction.