Novel Superoxide Dismutase Mimetics for Protection against Paraquat-induced Acute Renal Injury

Abstract

Paraquat-induced nephrotoxicity involves severe renal damage caused by reactive oxygen species (ROS), specifically by increasing superoxide (O2●-) generation in the kidney. While proven to be of benefit in animal models of organ injury involving O2●-, superoxide dismutase (SOD) and superoxide dismutase mimetics (SODm) can suffer problems regarding their bioavailability and toxicity. Since ROS has been incriminated in the pathogenesis of several disease conditions including acute kidney injury, the search for ideal SODm therefore continues unabated. Thus, the current study aims at investigating the therapeutic potential of Manganese (II) complexes of ethylenebis (oxyethylenenitrilo) tetraacetic acid (EGTA) and ethylenebis hydroxyphenylglycine (EHPG), novel SODm, against paraquat-induced nephrotoxicity using an in vivo rodent model. Administration of a single intraperitoneal dose of 10-50 or 100 mg/kg paraquat to male Wistar rats (200-250g) produced acute kidney injury within 48 and 24 hours respectively; as evidenced by a significant increase in serum creatinine, fractional excretion of sodium and a reduction in creatinine clearance. Unlike Mn (II)-EGTA (2mg/kg), Mn (II)-EHPG (4mg/kg) was able to significantly attenuate the acute kidney injury induced by 10-50 mg/kg paraquat. These complexes were not toxic at the doses examined unlike SOD or conventional SODm which can display pro-oxidant actions at higher concentrations. Since the clinical toxicity profiles of EGTA and EHPG are already known, these novel SODm particularly Mn (II)-EHPG could be beneficial in attenuating disease conditions involving ROS generation.

Keywords: Acute kidney injury, Oxidative stress, Paraquat, Superoxide anion, Superoxide dismutase mimetics