Sirtuin 7 Deficiency Reduces Inflammation and Tubular Damage Induced by an Episode of Acute Kidney Injury.

Andrea Sánchez-Navarro,Lilia G Noriega,Florencia Rosetti,Norma A Bobadilla,Johan Auwerx,Miguel Ángel Martínez-Rojas,Rosalba Pérez-Villalva,Abigail De La Cruz,Adrián Albarrán-Godinez

doi:10.3390/ijms23052573

Abstract

Acute kidney injury (AKI) is a public health problem worldwide. Sirtuins are a family of seven NAD+-dependent deacylases, Overexpression of Sirtuin 1, 3, and 5 protect against AKI. However, the role of Sirtuin 7 (Sirt7) in AKI is not known. Here, we analyzed how Sirt7 deficient mice (KO-Sirt7) were affected by AKI. As expected, wild-type and Sirt7 heterozygotes mice that underwent renal ischemia/reperfusion (IR) exhibited the characteristic hallmarks of AKI: renal dysfunction, tubular damage, albuminuria, increased oxidative stress, and renal inflammation. In contrast, the KO-Sirt7+IR mice were protected from AKI, exhibiting lesser albuminuria and reduction in urinary biomarkers of tubular damage, despite similar renal dysfunction. The renoprotection in the Sirt7-KO+IR group was associated with reduced kidney weight, minor expression of inflammatory cytokines and less renal infiltration of inflammatory cells. This anti-inflammatory effect was related to diminished p65 expression and in its active phosphorylation, as well as by a reduction in p65 nuclear translocation. Sirt7 deficient mice are protected from AKI, suggesting that this histone deacetylase promotes tubular damage and renal inflammation. Therefore, our findings indicate that Sirt7 inhibitors may be an attractive therapeutic target to reduce NFκB signaling.

Highlights

Acute kidney injury (AKI) affects 21% of hospitalized patients and up to 60% in critical care units [1,2]
We found less tubular damage in Sirtuin 7 (Sirt7) deficient mice, renal dysfunction (GFR) induced by IR was not alleviated, suggesting that this sirtuin has little effect on vasoconstrictor factors that are induced after AKI
One possible explanation for the renoprotection observed after IR in the Sirt7 deficient mice could be mediated by a compensatory overexpression of Sirt1 and Sirt3 that have been previously described as protectors from AKI [17–19]

Summary

Introduction

Acute kidney injury (AKI) affects 21% of hospitalized patients and up to 60% in critical care units [1,2]. Most of the AKI events are related to ischemic processes in which the hypoxic state, together with the resulting oxidative stress, leads to injury of proximal tubular epithelial cells [3–5]. These processes are accompanied by macrophage infiltration and inflammation [4,6]. The relevance of histone deacetylation modifications controlling cellular processes has been established; four types of deacetylases have been described and divided into class I, II, III, and IV. Class III deacetylases are known as sirtuins. Sirtuins are a family of seven NAD+-dependent deacetylases named from 1 to 7, with Sirtuin

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Conclusion