Sirtuin 7 Deficiency Ameliorates Cisplatin-induced Acute Kidney Injury Through Regulation of the Inflammatory Response

Yoshikazu Miyasato,Yoshihiro Komohara,Alessandro Ianni,Yoshifumi Sato,Takashige Kuwabara,Thomas Braun,Terumasa Nakagawa,Yutaka Kakizoe,Masashi Mukoyama,Kazuya Yamagata,Yuko Miyasato,Tatsuya Yoshizawa,Masataka Adachi

doi:10.1038/s41598-018-24257-7

Abstract

Cisplatin-induced acute kidney injury (AKI) has been recognized as one of cisplatin’s serious side effects, limiting its use in cancer therapy. Sirtuin 1 (SIRT1) and SIRT3 play protective roles against cisplatin-induced kidney injury. However, the role of SIRT7 in cisplatin-induced kidney injury is not yet known. In this study, we found that Sirt7 knockout (KO) mice were resistant to cisplatin-induced AKI. Furthermore, our studies identified that loss of SIRT7 decreases the expression of tumor necrosis factor-α (TNF-α) by regulating the nuclear expression of the transcription factor nuclear factor kappa B. It has been reported that cisplatin-induced nephrotoxicity is mediated by TNF-α. Our results indicate that SIRT7 plays an important role in cisplatin-induced AKI and suggest the possibility of SIRT7 as a novel therapeutic target for cisplatin-induced nephrotoxicity.

Highlights

In this study, we investigated the role of SIRT7 in renal injury in cisplatin nephrotoxicity using Sirt[7] KO mice
Double immunostaining for SIRT7 and Phaseolus vulgaris erythroagglutinin (PHA-E) lectin revealed that SIRT7 is expressed in proximal tubular cells (Fig. 1D)[16]
Consistent with LacZ staining in the inner medullary region, SIRT7 was expressed in Dolichos biflorus agglutinin (DBA; a marker of collecting duct cells)-positive collecting duct cells (Fig. 1D)[16]

Summary

Introduction

We investigated the role of SIRT7 in renal injury in cisplatin nephrotoxicity using Sirt[7] KO mice. We found that Sirt[7] KO mice showed protective effects against cisplatin-induced AKI. Our studies identified that the loss of SIRT7 decreases the expression of tumor necrosis factor-α (TNF-α), a critical proinflammatory cytokine in cisplatin-induced nephrotoxicity, by regulating the nuclear expression of the transcription factor nuclear factor kappa B (NF-κB). Our results indicate that SIRT7 plays an important role in cisplatin-induced AKI.

Methods

Results

Conclusion