Renoprotective Effect of Berberine in Cisplatin-Induced Acute Kidney Injury: Role of Klotho and the AMPK/mTOR/ULK1/Beclin-1 Pathway.

Abstract

Cisplatin (Cisp.) is a potent cancer drug, but its use is limited by acute kidney injury (AKI). Autophagy, a process that removes damaged proteins and maintains cellular homeostasis, has been shown to alleviate Cisp-induced AKI. The balance between autophagy and apoptosis is crucial to kidney protection. Treatment with Berberine, known for its antioxidant and anti-inflammatory effects in nephrotoxicity models, was studied for its potential to enhance autophagy in Cisp-induced AKI. Treatment with Berberine (Berb) upregulated Klotho gene expression, enhancing autophagy as indicated by elevated protein levels of pS486-AMPK, pS638-ULK1, and Beclin-1, accompanied by a decrease in pS248-mTOR protein expression. Also, Berb mitigated oxidative stress by reducing elevated MDA levels and boosting SOD activity, which in turn suppressed inflammation by down-regulating HMGB1 and RAGE gene expression, as well as reducing pS536-NF-κB and IL-6 protein contents. Additionally, Berb reduced apoptosis by increasing Bcl-2 and decreasing Bax. This coordinated action preserved kidney function, evidenced by reductions in early injury markers (cystatin C, KIM-1, NGAL) and late markers (creatinine, BUN), along with attenuation of histopathological alterations. The use 3-MA, autophagy inhibitor, nullified these protective effects, highlighting Berb's role in promoting autophagy, reducing oxidative stress, inflammation, and apoptosis, and preserving renal health in Cisp-induced AKI.