nifuroxazide and Diabetic-Nephropathies

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. Moreover,it is amongst the most common causes of end-stage renal failure. Inflammation is a crucial player in both development and progression of DN. JAK2/STA3 is a pleotropic cascade reported to regulate diverse inflammatory events. Previous studies reported involvement of JAK2/STA3 signal transduction pathway in diabetes-associated renal injury. In the current study, the inhibitory effect of nifuroxazide (25 mg/kg/day, orally) against inflammatory condition associating diabetic kidney progression in rats was evaluated. The underlying hypothesis is mainly via the inhibitory effect of nifuroxazide on STAT3 signaling. Results revealed that nifuroxazide effectively inhibited STAT3 activation in diabetic male rats, improved glomerular filtration function, protected against diabetes-induced histopathological and ultramicroscopic structural alterations. Further, nifuroxazide treatment significantly reduced renal macrophage infiltration and fibrosis and decreased mRNA and protein levels of TNF-α and IL-18 in diabetic renal tissue. The current findings shed the light on nifuroxazide's efficacy as an alternative anti-inflammatory therapy to hinder the development and progression of DN in diabetic patients mainly via STAT3 inhibition.

Topics: Animals; Anti-Inflammatory Agents; Blood Urea Nitrogen; Creatine; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Fibrosis; Hydroxybenzoates; Interleukin-18; Janus Kinase 2; Kidney; Kidney Function Tests; Macrophages; Male; Microscopy, Electron; Nitrofurans; Rats; Signal Transduction; STAT3 Transcription Factor; Streptozocin; Tumor Necrosis Factor-alpha

The prevalence of diabetes mellitus (DM) is drastically increased worldwide. Diabetic nephropathy (DN) is a microvascular complication of DM and a common cause of end stage renal disease (ESRD). DN has been recently reported as the most common cause among ESRD patients. Shortage of a definitive cure for DN and the social and economic burden of this disease provide considerable impetus for development of new therapies. In the present study, we evaluated the effect of nifuroxazide, a potent inhibitor of Janus kinase/signal transducers and activators of transcription (JAK2/STAT3), on nuclear factor kappa B (NFκB), oxidative stress, and apoptosis in diabetic kidney. Following induction of diabetes by single dose of streptozotocin (50 mg/kg), nifuroxazide was administrated to diabetic rats (25 mg/kg/day, orally) for 8 weeks. Our results showed that nifuroxazide treatment, attenuated diabetes-induced damage in renal structure, ameliorated oxidative stress, triggered antioxidant defense, reduced NFκB nuclear translocation and cleaved caspase-3 expression and down regulated the activity of apoptotic enzymes (caspase-3/caspase-8/caspase-9) in diabetic kidney. In conclusion, nifuroxazide exhibited renoprotective effect in diabetic kidney via dampening NFκB activation, oxidative stress, and apoptosis.

Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Hydroxybenzoates; Janus Kinase 2; Kidney; Male; NF-kappa B; Nitrofurans; Oxidative Stress; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor