Influence of the renin-angiotensin system on epidermal growth factor expression in normal and cyclosporine-treated rat kidney

Background. Epidermal growth factor (EGF) plays an important role in renal tubular regeneration after ischemic injury in kidney. The present study reports the association between the renin-angiotensin system (RAS) and EGF, and the effect of angiotensin II blockade with losartan (LSRT) on EGF expression in an experimental model of chronic cyclosporine (CsA) nephrotoxicity in rats. Methods. Two separate experiments were performed. In the first experiment, rats on the normal-salt diet (NSD; 0.3%) or low-salt diet (LSD; 0.05%) were treated with or without LSRT for four weeks. In the second experiment, rats on the NSD or LSD were given vehicle (VH group, olive oil, 1 mg/kg per day) or CsA (15 mg/kg per day) or CsA (15 mg/kg per day) plus LSRT (100 mg/L per day). Renal function, histopathology, TUNEL staining, plasma renin activity (PRA), and the expression of renin and EGF were studied. Results. Normal rats on the LSD showed significantly increased EGF expression (cortex, 2.6-fold; medulla, 1.7-fold) and significantly decreased EGF expression with the LSRT treatment compared with the rats treated with the NSD (cortex, 74.8 vs. 10%; medulla, 22.5 vs. 5%). In contrast, the CsA-treated rats on the LSD had a significantly lower EGF expression (cortex, 98 vs. 53%; medulla, 94 vs. 14%); however, concomitant administration of LSRT increased the EGF expression (cortex, 91- vs. 3.8-fold; medulla, 19- vs. 2.4-fold) compared with the rats on the NSD. In the normal and CsA-treated LSD rats, EGF expression was well correlated with PRA. In addition, EGF expression was well correlated with the interstitial fibrosis score (r = 0.664, P < 0.01) or number of TUNEL-positive cells (r = 0.822, P < 0.01) in CsA-treated LSD rats. Conclusions. These results suggest that angiotensin II blockade with LSRT decreases EGF expression in normal rats on the LSD, but it protects EGF expression in CsA-induced nephrotoxicity. This finding provides a new perspective on the renoprotection of angiotensin II blockade in chronic CsA nephrotoxicity.