Renal tubular arginase-2 participates in the formation of the corticomedullary urea gradient and attenuates kidney damage in ischemia-reperfusion injury in mice.

Camille Ansermet,Hikari A Yoshihara,Jean‐Luc Barras,Nicolas Dattner,Samuel Rotman,Svetlana Nikolaeva,Sylviane Lagarrigue,Gabriel Centeno,Sylvain Pradervand,Dmitri Firsov,Francesca Amati

doi:10.1111/apha.13457

Abstract

Arginase 2 (ARG2) is a mitochondrial enzyme that catalyses hydrolysis of l-arginine into urea and l-ornithine. In the kidney, ARG2 is localized to the S3 segment of the proximal tubule. It has been shown that expression and activity of this enzyme are upregulated in a variety of renal pathologies, including ischemia-reperfusion (IR) injury. However, the (patho)physiological role of ARG2 in the renal tubule remains largely unknown. We addressed this question in mice with conditional knockout of Arg2 in renal tubular cells (Arg2lox/lox /Pax8-rtTA/LC1 or, cKO mice). We demonstrate that cKO mice exhibit impaired urea concentration and osmolality gradients along the corticomedullary axis. In a model of unilateral ischemia-reperfusion injury (UIRI) with an intact contralateral kidney, ischemia followed by 24hours of reperfusion resulted in significantly more pronounced histological damage in ischemic kidneys from cKO mice compared to control and sham-operated mice. In parallel, UIRI-subjected cKO mice exhibited a broad range of renal functional abnormalities, including albuminuria and aminoaciduria. Fourteen days after UIRI, the cKO mice exhibited complex phenotype characterized by significantly lower body weight, increased plasma levels of early predictive markers of kidney disease progression (asymmetric dimethylarginine and symmetric dimethylarginine), impaired mitochondrial function in the ischemic kidney but no difference in kidney fibrosis as compared to control mice. Collectively, these results establish the role of ARG2 in the formation of corticomedullary urea and osmolality gradients and suggest that this enzyme attenuates kidney damage in ischemia-reperfusion injury.

Highlights

Role of ARG2 in the early phase of renal injury triggered by IR: 24-hour reperfusion
Arginase-2 is an extensively studied enzyme involved in a wide variety of biological processes and pathophysiological conditions
The present study supports this hypothesis, thereby providing new insight into the mechanism of urine formation. Differ from those of Huang and colleagues who found in Arg2null mice that ARG2 negatively regulates AQP2 expression and water reabsorption in the kidney

Summary

Introduction

Role of ARG2 in the early phase of renal injury triggered by IR: 24-hour reperfusion. Arg[2] mRNA expression was significantly increased in the left ischemic kidney of control mice as compared to the contralateral (right) kidney and to kidneys from sham-operated animals. Immunohistochemical analysis revealed dramatically increased ARG2 expression in the medulla of the left ischemic kidney in control mice, as compared to the right kidney (Figure 2C). TUNEL assay showed a diffuse staining of damaged tubules in kidneys of UIRI-subjected control and cKO mice (Figures 3D and 3E, respectively, and Supplementary Figure 2), characteristic of necrotic cell death. Quantitation of TUNEL staining revealed a similar trend towards higher cellular damage in UIRI-subjected cKO mice (p=0.058, Figure 3F). Expression levels of most tested early tissue AKI biomarkers (Kim-1, Il-6 and Tnf-a) were increased in left ischemic kidneys of both genotypes but not different between control and cKO mice (Supplementary Figure 3)

Methods

Results

Conclusion