Dihydromyricetin protects against gentamicin-induced nephrotoxicity via upregulation of renal SIRT3 and PAX2.

Gentamicin-induced nephrotoxicity limits its widespread use as an effective antibacterial agent. Oxidative stress, inflammatory cytokines and apoptotic cell death are major participants in gentamicin-induced nephrotoxicity. We therefore, investigated whether dihydromyricetin (DHM), the antioxidant and anti-inflammatory flavonoid, could protect against the nephrotoxic effects of gentamicin. Male Wistar rats administrated gentamicin (100 mg/kg/day, i.p.) for 8 days. DHM (400 mg/kg, p.o.) was concurrently given with gentamicin for 8 days. Control group received the vehicle of DHM and gentamicin. Histopathological examinations, biochemical measurements and immunohistochemical analyses were done at the end of the study. Treatment with DHM improved the gentamicin induced deterioration of renal functions; serum levels of urea, creatinine and cystatin–C as well as urinary levels of Kim-1 and NGAL, the sensitive indicators for early renal damage, were declined. Additionally, DHM abrogated gentamicin-induced changes in kidney morphology. These nephroprotective effects were possibly mediated via decreasing renal gentamicin buildup, activating the antioxidant enzymes GSH, SOD and CAT and decreasing lipid peroxidation and nitric oxide levels. Further, DHM suppressed renal inflammation and apoptotic cell death by decreasing the expression of nuclear factor-kappa B (NF-κB), TNF-alpha and caspase-3. These effects were correlated to the upregulation of renal SIRT3 expression. Also, DHM activated the regeneration and replacement of injured tubular cells with new ones via enhancing PAX2 expression. DHM is a promising therapeutic target that could prevent acute renal injury induced by gentamicin and help renal tubular cells to recover through its antioxidant, anti-inflammatory and antiapoptotic properties. Fig. 7. Graphical abstract illustrating the effect of treatment with DHM 400 mg/kg on GTN-induced nephrotoxicity. DHM was concurrently given with GTN 100 mg/kg/day for 8 days. Serum, urine and kidney tissues were collected for biochemical, immunohistochemical and histopathological analyses. DHM restored renal functions and prevented the GTN-induced renal damage by increasing expression of SIRT3 which is correlated to enhanced expression of antioxidant enzyme, SOD, CAT and GSH and deceased renal MDA and NO. Levels of caspase 3, NF-kB, TNF-α were attenuated in DHM treated group. Additionally, PAX2 expression was upregulated by DHM to enhance the regeneration of renal tubular cells and the recovery from GTN-induced nephrotoxicity. [Display omitted] [ABSTRACT FROM AUTHOR]