Ability of a small, basic protein isolated from Russell's viper venom (Daboia russelli russelli) to induce renal tubular necrosis in mice

Russell's viper venom (RVV) induced acute renal failure involves both direct and indirect nephrotoxic actions where the specific component/s are yet to be identified. A basic cytotoxin of 7.2 kDa (RVV-7) has been identified as potential nephrotoxin. Autoradiographic experiments demonstrated that only RVV-7 among RVV toxins binds specifically to mice kidney membrane. Homogeneous preparation of RVV-7 confirmed its necrotic cell killing property having EC50 of 4.79±3.28 μM. Tissue distribution kinetics of RVV-7 in mice showed its higher localization in kidney compared to blood and liver. Role of inherent factor responsible for its localization in kidney was assessed after chemical inactivation of its cytotoxic activity. Cytotoxicity was neutralized by histidine modification but consequent alteration of in vivo distribution was insignificant. Classical concept of glomerular capillary wall (GCW) permselectivity barrier denotes that apart from size selectivity, GCW also restricts anionic proteins from filtration. Reducing the pI of RVV-7 by chemical manipulation of its surface positive charges resulted to decreased accumulation in kidney. Histological observations of kidney from mice treated in vivo with RVV-7 showed degenerated tubular epithelium. These findings indicate that basic character and small size of RVV-7 are favorable for its rapid accumulation in kidney leading to necrotic destruction of tubular epithelium.