Celastrol Mitigates Colistin-Induced Renal Toxicity in Rats via Modulating Nrf-2/HO-1 and NF-κB Signaling Pathways

Colistin (CST) is an effective antibiotic that decreases the mortality rates accompanying nosocomial infection with multidrug-resistant resistant bacteria. However, its use is limited because of the high potential of inducing severe nephrotoxicity. Celastrol (CELA) is a medicinally promising triterpenoid and the most abundant bioactive constituent of the root pulps of the widely used Chinese herb, Tripterygium wilfordii. CELA confers cellular protection because of its antioxidant, anti-inflammatory, and antiapoptotic activities. The current study aimed to investigate the potential nephroprotective effects of CELA against CST-induced nephrotoxicity. Rats were divided into five groups, and treated as follows: Group One received vehicles only; Group Two received CELA only; Group Three received CST only and Groups Four and Five received CST and CELA (0.5 or 1 mg/kg). Microscopical examination of H&E-stained kidney sections indicated that CST-only-treated animals exhibited distortion in the renal histological features; Also, Masson's trichrome, Picrosirius Red, and Periodic acid-Schiff staining highlighted fibrotic changes. This was associated with increased kidney serum markers (urea, creatinine, and cystatin C), induced oxidative stress (increased levels of MDA, decreased activities of SOD and CAT, and reduced the protein levels of Nrf-2 and HO-1), increased the immunoreactivity of the inflammatory markers (COX-2, iNOS, TNF-α, and NF-κB), and stimulated apoptosis (increased the transcription of Bax and CASP3 and decreased that of Bcl-2). In contrast, pretreatment with CELA significantly reduced the histopathological changes, oxidative stress, inflammation, and apoptosis. Therefore, CELA showed significant renal protection against CST-induced kidney injury.