INFLUENCE OF HYPERGLYCEMIA ON OXIDATIVE STRESS AND DNAase-MEDIATED GENOMIC FRAGMENTATION COUPLED WIT

Abstract

Diclofenac (DCLF) is a potent inhibitor of prostaglandin synthesis and an established antipyretic and analgesic agent. It also has a nephrotoxic profile caused by generation of reactive oxygen species and enhanced apoptotic DNA fragmentation. The specific goals of this investigation were to determine: (i) sensitivity of hyperglycemic mice to nephrotoxic doses of DCLF, (ii) whether hyperglycemia modulates genomic DNA-fragmenting potency of DCLF in kidney, (iii) whether hyperglycemia would increase DCF-induced oxidative stress in kidney and (iv) whether hyperglycemia can alter apoptotic and necrotic death of kidney cells. Male ICR CD-I mice were divided into normal and diabetic groups. Diabetes was induced by administering 100 mg/kg streptozotocin. Both normal and diabetic groups were divided into sub-groups on basis of nephrotoxic doses of DCLF i.e., 100 and 200 mg/kg i.p. The mice were sacrificed after 24-hrs and determined blood urea nitrogen (BUN), lipid peroxidation level and caspase-activated DNAase-mediated genomic DNA fragmentation. In addition, kidney tissues were examined histopathologically and checked for DNA damage. The results obtained showed that DCLF is a potent nephrotoxic agent as it increases BUN and powerfully induces oxidative stress depicted by significant increase in malandialdehyde (MDA) level which lead to massive DNA fragmentation coupled with apoptotic and necrotic cell deaths in both diabetic and non-diabetic groups in vivo. In addition, data have indicated that DCF causes greater nephrotoxicity in diabetics as compared to non-diabetics as shown by higher values of BUN, LPG and genomic DNA fragmentation.