Abstract
Silybin is a secondary metabolite isolated from the seeds of blessed milk thistle (Silybum marianum) that has anti-inflammatory, antioxidative, antifibrotic, and antitumor properties. Here, we showed that silybin protected against cisplatin-induced acute kidney injury (AKI) by improving mitochondrial function through the regulation of sirtuin 3 (SIRT3) expression. Male SV129 and SIRT3 knockout (KO) mice were administered a single intraperitoneal (i.p.) injection of cisplatin with or without treatment with silybin. Moreover, cultured HK2 cells were used to evaluate mitochondrial morphology and function. Our data suggested that silybin enhanced SIRT3 expression after cisplatin administration both in vivo and in vitro. Silybin treatment improved mitochondrial function and bioenergetics in wild-type, but not SIRT3-defective, cells and mice. Moreover, we demonstrated that silybin markedly attenuated cisplatin-induced AKI and tubular cell apoptosis and improved cell regeneration in a SIRT3-dependent manner. Collectively, these results suggest that silybin is a pharmacological activator of SIRT3 capable of protecting against cisplatin-induced tubular cell apoptosis and AKI by improving mitochondrial function. Thus, silybin could serve as a potential clinical renoprotective adjuvant treatment in cisplatin chemotherapy.
Highlights
Cisplatin is one of the most efficient and widely used anticancer chemotherapy drugs in the clinic for the treatment of bladder cancer, non-small cell lung cancer and other solid tumors (Siddik, 2003)
The present study confirmed that sirtuin 3 (SIRT3) plays an important role in regulating mitochondrial function in renal tubular epithelial cells
The results showed that a decrease in SIRT3 expression in renal tubular epithelial cells led to a reduction in mitochondrial bioenergetics in the cisplatin-induced acute kidney injury (AKI) mice
Summary
Cisplatin is one of the most efficient and widely used anticancer chemotherapy drugs in the clinic for the treatment of bladder cancer, non-small cell lung cancer and other solid tumors (Siddik, 2003). Its use is frequently limited by its adverse effects, such as neurotoxicity, bone marrow suppression and nephrotoxicity. Among these effects, nephrotoxicity is the major limiting factor for cisplatin therapy (Arany and Safirstein, 2003). The nephrotoxic effect of cisplatin is cumulative and dose-dependent, and it often necessitates dose reduction or withdrawal (Pabla and Dong, 2008). It has been suggested that oxidative stress, a redox state imbalance, impaired energetic metabolism, cell apoptosis and inflammation are likely associated with cisplatin-induced acute kidney injury (AKI) (Miller et al, 2010).
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