Direct transfer of hepatocyte growth factor gene into kidney suppresses cyclosporin A nephrotoxicity in rats.

Abstract

The clinical utility of cyclosporin A (CsA) has been limited by its nephrotoxicity, which is characterized by tubular atrophy, interstitial fibrosis and progressive renal impairment. Hepatocyte growth factor (HGF), which plays diverse roles in the regeneration of the kidney following acute renal failure, has been reported to protect against and salvage renal injury by acting as a renotropic and anti-fibrotic factor. Here, we investigated protective effects of HGF gene therapy on CsA-induced nephrotoxicity by using an electroporation-mediated gene transfer method. CsA was orally administered as a daily dose of 30 mg/kg in male Sprague-Dawley rats receiving a low sodium diet (0.03% sodium). Plasmid vector encoding HGF (200 micro g) was transferred into the kidney by electroporation. HGF gene transfer resulted in significant increases in plasma HGF levels. Morphological assessment revealed that HGF gene transfer reduced CsA-induced initial tubular injury and inhibited interstitial infiltration of ED-1-positive macrophages. In addition, northern blot analysis demonstrated that cortical mRNA levels of TGF-beta and type I collagen were suppressed in the HGF group. Finally, HGF gene transfer significantly reduced striped interstitial phenotypic alterations and fibrosis in CsA-treated rats, as assessed by alpha-smooth muscle actin expression and Masson's trichrome staining. These results suggest that HGF may prevent CsA-induced tubulointerstitial fibrosis, indicating that HGF gene transfer may provide a potential strategy for preventing renal fibrosis.