Carbocisteine Confers Renoprotection in Streptozotocin-Induced Diabetic Nephropathy Through Sirt-1/Nrf-2-Dependent Inhibition of NLRP3 Inflammasome Activation.

Abstract

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, largely driven by oxidative stress and inflammation. This study evaluated the protective role of carbocisteine, a mucolytic with antioxidant and anti-inflammatory properties, against streptozotocin (STZ)-induced DN in rats. Male Sprague-Dawley rats were divided into four groups: normal, diabetic, carbocisteine (250 mg/kg), and carbocisteine (500 mg/kg). After 8 weeks, diabetic rats showed significant hyperglycemia, weight loss, renal dysfunction (elevated serum creatinine, BUN, and urinary protein), oxidative stress (increased MDA, decreased GSH), and upregulation of inflammatory mediators; IL-1β, IL-6, and TNF-α, along with downregulation of Sirt-1 and Nrf-2 expression and upregulation of NLRP3 and caspase-1. Moreover, diabetic rats exhibited a pro-apoptotic shift, characterized by increased Bax and decreased Bcl-2 expression. Histopathology revealed mesangial expansion, tubular degeneration, and interstitial fibrosis. Carbocisteine treatment, particularly at the high dose, significantly improved renal function, attenuated oxidative and inflammatory responses, restored Sirt-1 and Nrf-2 levels, suppressed NLRP3/caspase-1 activation, and reversed the Bax/Bcl-2 imbalance, thereby ameliorating histopathological damage. These findings suggest that carbocisteine exerts nephroprotective effects in diabetic rats through modulation of the Sirt-1/Nrf-2/NLRP3/caspase-1 signaling axis and regulation of the Bax/Bcl-2 apoptotic pathway, highlighting its potential as a promising adjunct therapy for DN.