Activated SIRT1 and SIRT6 by Nrf2 Activator Attenuated Cisplatin-Induced Acute Nephrotoxicity in Mice

Abstract

Background: Cisplatin (CDDP) is a widely used cancer therapy drug that exhibits major side effects in normal tissues, such as nephrotoxicity in kidneys. The Nrf2 signaling pathway, a regulator of mitochondrial dysfunction, oxidative stress and inflammation, is a potential therapeutic target in CDDP-induced nephrotoxicity. Methods: We explored the underlying mechanisms in wild-type (WT) and Nrf2-/- mice on CDDP-induced renal dysfunction in vivo. As Daphnetin (Daph) is a Nrf2 activator, here, we assessed the effects of Daph against CDDP-induced nephrotoxicity using HK-2 cells. Results: We found that Nrf2 deficiency aggravated CDDP-induced nephrotoxicity, and Daph treatment significantly ameliorated the renal injury characterized by biochemical markers in WT mice and reduced the CDDP-induced cell damage. In terms of the mechanism, Daph upregulated the SIRT1 and SIRT6 expression in vivo and in vitro. In addition, Daph activated Nrf2 translocation and the expression of its regulated antioxidant enzymes HO-1 and NQO1, whereas it inhibited NOX4 expression, thus decreasing oxidative stress and mitochondrial dysfunction. Moreover, Daph attenuated CDDP-induced activation of HMGB1 and the phosphorylation of JNK, p38, ERK and NF-κB to suppress inflammation, as well as decreased CDDP-induced upregulation of cleaved caspase-3, p53 and the Bax/Bcl2 ratio to inhibit apoptosis. Notably, the protective effects of Daph in WT mice were completely abrogated in Nrf2 -/- mice. Moreover, Daph enhanced, rather than attenuated, the tumoricidal effect of CDDP. Conclusions: Our findings indicate the protective effect of Daph on CDDPinduced nephrotoxicity by SIRT1 and SIRT6 mediated-Nrf2 activation which regulates inflammation, mitochondrial dysfunction and apoptosis. Funding Statement: This work was supported by the National Natural Science Foundation of China (Grant No. 81603174) and the General Financial Grant from the China Postdoctoral Science Foundation (Grant No. 168847). Declaration of Interests: The authors declare that they have no competing interests Ethics Approval Statement: All animal studies were reviewed and approved by the Animal Welfare and Research Ethics Committee of Jilin University.