Background: The clinical utility of cyclosporine A (CsA) has been limited by its nephrotoxicity, which is characterized by tubular atrophy, interstitial fibrosis, and progressive renal impairment. Hepatocyte growth factor (HGF) has been reported to protect and salvage from renal injury as a renotropic and antifibrotic factor. Here, we investigated protective effects of HGF gene therapy on rat CsA-induced nephrotoxicity using electroporation-mediated gene transfer.
Method: CsA was subcutaneously administered daily under low sodium diet, and HGF gene was transferred into skeletal muscle by electroporation on days 7 and 14. We also examined the antiapoptotic mechanism of HGF using human proximal tubular epithelial cells.
Results: HGF gene transfer rescued CsA-induced initial tubular injury and suppressed interstitial infiltration of ED-1-positive macrophages in CsA-induced nephrotoxicity. In addition, HGF significantly inhibited tubular cell apoptosis, and increased the number of proliferating tubular epithelial cells. In vitro studies suggest that HGF executes the antiapoptotic function by enhancing the phosphorylation of Akt and Bcl-2. Northern blot analysis demonstrated that HGF gene transfer suppressed cortical mRNA levels of transforming growth factor-beta (TGF-beta). Consequently, HGF gene transfer significantly reduced a striped interstitial phenotypic alteration and fibrosis.
Conclusion: We demonstrated that HGF gene transfer reduced CsA-induced tubular cell apoptosis and interstitial fibrosis. HGF gene transfer could be a potential strategy for preventing renal fibrosis.