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.