Betaine alleviates doxorubicin‐induced nephrotoxicity by preventing oxidative insults, inflammation, and fibrosis through the modulation of Nrf2/HO−1/NLRP3 and TGF‐β expression

Abstract

AbstractDoxorubicin (Dox) is an anthracycline antibiotic used to treat various cancers and shows severe toxicity in multiple organ systems, including kidneys. Evidence shows that betaine's antioxidant and anti‐inflammatory properties could prevent the onset of several disorders. Hence, the present study aims to investigate the therapeutic potential of betaine on Dox‐induced nephrotoxicity (DIN). Nephrotoxicity was induced in male Sprague Dawley rats using Dox at a dose of 4 mg/kg (cumulative dose: 20 mg/kg) by the intraperitoneal route and cotreated with betaine through oral gavage (200 and 400 mg/kg) for 28 days. At the end of the experiment, biochemical, oxidative stress parameters, histopathology, and qRT‐PCR were performed. DIN was indicated by elevated serum creatinine, urea, and decreased albumin levels representing kidney damage; the histopathological lesions (increased capsular space, renal tubule damage, and fibrosis) in renal tissues supported these biochemical findings. Interestingly, betaine treatment improves these alterations in Dox‐treated rats. Further, betaine treatment decreases the lipid peroxidation and nitrite concentration and increases the superoxide dismutases and catalase enzyme concentration in Dox‐treated rats. Fascinatingly, at the molecular level, DIN in rats shows upregulation of the Nrf2/HO‐1 gene, while betaine treatment attenuated its expression along with the downregulation of inflammatory genes (NLRP3, TLR‐4, TNF‐α, and IL‐6) and fibrosis‐related genes (TGF‐β and Acta2) expression in Dox‐treated rats. These results showed that betaine has reno‐protective properties by reducing inflammatory and fibrotic mediators and enhancing antioxidant capacity in the renal tissue of rats treated with Dox. We believe betaine can be exploited as a dietary supplement to attenuate DIN.