The Absence of Endothelial Sodium Channel α (αENaC) Reduces Renal Ischemia/Reperfusion Injury.

Antoine Tarjus,Jonatan Barrera-Chimal,Cecilia González-Rivas,Benjamin Bonnard,Frédéric Jaisser,Isabel Amador-Martínez,Rebeca López-Marure

doi:10.3390/ijms20133132

Abstract

The epithelial sodium channel (ENaC) has a key role in modulating endothelial cell stiffness and this in turn regulates nitric oxide (NO) synthesis. The physiological relevance of endothelial ENaC in pathological conditions where reduced NO bioavailability plays an essential role remains largely unexplored. Renal ischemia/reperfusion (IR) injury is characterized by vasoconstriction and sustained decrease in renal perfusion that is partially explained by a reduction in NO bioavailability. Therefore, we aimed to explore if an endothelial ENaC deficiency has an impact on the severity of renal injury induced by IR. Male mice with a specific endothelial sodium channel α (αENaC) subunit gene inactivation in the endothelium (endo-αENaCKO) and control littermates were subjected to bilateral renal ischemia of 22 min and were studied after 24 h of reperfusion. In control littermates, renal ischemia induced an increase in plasma creatinine and urea, augmented the kidney injury molecule-1 (Kim-1) and neutrophil gelatinase associated lipocalin-2 (NGAL) mRNA levels, and produced severe tubular injury. The absence of endothelial αENaC expression prevented renal tubular injury and renal dysfunction. Moreover, endo-αENaCKO mice recovered faster from renal hypoxia after the ischemia episode as compared to littermates. In human endothelial cells, pharmacological ENaC inhibition promoted endothelial nitric oxide synthase (eNOS) coupling and activation. Altogether, these data suggest an important role for endothelial αENaC in kidney IR injury through improving eNOS activation and kidney perfusion, thus, preventing ischemic injury.

Highlights

Acute kidney injury (AKI) induced by ischemia/reperfusion (IR) is a major clinical concern that affects around 10% of hospitalized patients and up to 40–60% of critical care patients [1,2]
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On the other hand, decreased endothelial αENaC expression/activity led to an increase of eNOS-dependent NO production [30]

Summary

Introduction

Acute kidney injury (AKI) induced by ischemia/reperfusion (IR) is a major clinical concern that affects around 10% of hospitalized patients and up to 40–60% of critical care patients [1,2]. A hallmark of renal IR is the prolonged reduction in the renal blood flow and oxygen supply to the kidney [4,5,6]. The reduction in the kidney perfusion is triggered by vasoconstriction due to an imbalance in vasoactive factors. NO administration to patients undergoing multiple valve replacement surgeries reduced post-operative AKI incidence and transition to chronic kidney disease stage 3 after one year of the surgery [17]

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