SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model.

Siqi Xu,Xingui Dai,Zhenhua Zeng,Zhongqing Chen,Qin Zhang,Youguang Gao,Siwei Wei,Ke-Seng Zhao

doi:10.1155/2016/7296092

Abstract

Sepsis often results in damage to multiple organ systems, possibly due to severe mitochondrial dysfunction. Two members of the sirtuin family, SIRT1 and SIRT3, have been implicated in the reversal of mitochondrial damage. The aim of this study was to determine the role of SIRT1/3 in acute kidney injury (AKI) following sepsis in a septic rat model. After drug pretreatment and cecal ligation and puncture (CLP) model reproduction in the rats, we performed survival time evaluation and kidney tissue extraction and renal tubular epithelial cell (RTEC) isolation. We observed reduced SIRT1/3 activity, elevated acetylated SOD2 (ac-SOD2) levels and oxidative stress, and damaged mitochondria in RTECs following sepsis. Treatment with resveratrol (RSV), a chemical SIRT1 activator, effectively restored SIRT1/3 activity, reduced acetylated SOD2 levels, ameliorated oxidative stress and mitochondrial function of RTECs, and prolonged survival time. However, the beneficial effects of RSV were greatly abrogated by Ex527, a selective inhibitor of SIRT1. These results suggest a therapeutic role for SIRT1 in the reversal of AKI in septic rat, which may rely on SIRT3-mediated deacetylation of SOD2. SIRT1/3 activation could therefore be a promising therapeutic strategy to treat sepsis-associated AKI.

Highlights

Sepsis is a frequently fatal condition characterized by uncontrolled and adverse host reactions to microbial infection [1], accounting for more than $20 billion (5.2%) of total US hospital costs in 2011 [2]
SIRT1 Activity Was Decreased in Renal Tissue following cecal ligation and puncture (CLP)
To determine whether SIRT1 is involved in the pathogenesis of sepsis-induced acute kidney injury (AKI), we studied both the activity and protein expression of SIRT1 in renal tissue (Figure 1)

Summary

Introduction

Sepsis is a frequently fatal condition characterized by uncontrolled and adverse host reactions to microbial infection [1], accounting for more than $20 billion (5.2%) of total US hospital costs in 2011 [2]. The current consensus is that the development of sepsis is characterized by multiple organ dysfunction [1]. The kidney is frequently affected during sepsis, and acute kidney injury (AKI) is a common occurrence during the pathogenesis of sepsis [5]. Tubular cells exhibit reduced oxygen consumption in response to sepsis, indicating severe mitochondrial dysfunction (MD) [6]. Our previous studies have shown that severe MD in renal tubular epithelial cells accelerates AKI in a rat model of sepsis [7]

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