Modulating SIRT1, Nrf2, and NF-xB signaling pathways by bergenin ameliorates the cadmium-induced nephrotoxicity in rats

In light of the current industrial evolution, exposure to cadmium has become a significant public health concern. Cadmium accumulates in the renal tubular cells and causes nephrotoxicity largely through disruption of the redox homeostasis, induction of inflammation, and suppression of the histone deacetylase SIRT1 expression. The current work aimed at exploring the protective capability of bergenin, a naturally-occurring methyl gallic acid derivative, against the cadmium-evoked nephrotoxicity. Male Wistar rats were treated either with cadmium alone or with cadmium and bergenin for a 7-day experimental period followed by collection of kidney and blood specimens that were subjected to biochemical, molecular, and histological investigations. The results revealed the ability of bergenin to improve the renal functions in the cadmium-intoxicated rats as evidenced by increased glomerular filtration rate, and decreased serum creatinine and blood urea nitrogen. Equally important, bergenin reduced the renal tissue injury and enhanced its redox homeostasis as indicated by decreased protein expression of the kidney injury marker KIM-1, reduced lipid peroxidation, and improved antioxidant potential and histopathological picture of the renal tissues. Mechanistically, bergenin reduced the renal tissue cadmium content, markedly up-regulated protein expression of SIRT1 that regulates inflammation and the redox status of the renal tissues. Additionally, it improved the expression of the major antioxidant transcription factor Nrf2 and its responsive gene products heoxygenase-1 and NAD(P)H quinone dehydrogenase 1 in the cadmium-intoxicated rats. In the same context, bergenin down-regulated the acetylation and the nuclear translocation of the inflammatory transcription factor NF-xB and reduced levels of its responsive gene products TNF-a and IL-113, as well as the activity of the inflammatory cell infiltration biomarker myeloperoxidase. Collectively, the current study underscores the ameliorating activity of bergenin against the cadmium-evoked nephrotoxicity and high-lights modulation of SIRT1, Nrf2, and NF-xB signaling as potential underlining molecular mechanisms.