FPTIII Mitigates Peroxisome-Mediated Oxidative Stress in Kidneys of Spontaneously Hypertensive Diabetic Rats

Abstract

Aim: Peroxisomes are known to play a role in cellular oxidative stress during pathogenesis of diabetes and hypertension. We reported earlier that FPTIII (a farnesyl protein transferase inhibitor) attenuates ischemia-reperfusion injury and renal dysfunction in diabetic hypertensive (DH) rats. In this study, we have examined the effect of FPTIII on peroxisomal enzymes in relation to oxidative stress in kidneys of DH rats. Methods: Male Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were treated with streptozotocin (STZ) and/or FPTIII. Activities of key peroxisomal enzymes, catalase, acyl-CoA oxidase and β-oxidation of lignoceric acid were measured in kidney homogenates. Lipid peroxidation in kidney was measured by malondialdehyde (MDA) assay. Results: Catalase activity was significantly (p < 0.01) reduced in diabetic WKY or SHR, and FPTIII markedly attenuated (p < 0.01) diabetes-induced inhibition of catalase. FPTIII also reduced STZ-induced increase in acyl-CoA oxidase activity. Fatty acid β-oxidation and lipid peroxides were significantly increased in kidneys of DH rats. FPTIII reduced (p < 0.01) diabetes and hypertension-induced increase in fatty acid oxidation and lipid peroxides. Conclusion: Our results suggest that farnesyl transferase inhibition modulates peroxisome enzyme activities and alleviates oxidative stress, thus providing a possible mechanism for reported FPTIII-mediated protection against renal dysfunction in DH rats.