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Renal tubular arginase‐2 participates in the formation of the corticomedullary urea gradient and attenuates kidney damage in ischemia‐reperfusion injury in mice
Author(s) -
Ansermet Camille,
Centeno Gabriel,
Lagarrigue Sylviane,
Nikolaeva Svetlana,
Yoshihara Hikari A.,
Pradervand Sylvain,
Barras JeanLuc,
Dattner Nicolas,
Rotman Samuel,
Amati Francesca,
Firsov Dmitri
Publication year - 2020
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.13457
Subject(s) - arginase , kidney , ischemia , acute kidney injury , endocrinology , medicine , renal function , reperfusion injury , renal ischemia , fibrosis , chemistry , arginine , biochemistry , amino acid
Aim 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. Methods We addressed this question in mice with conditional knockout of Arg2 in renal tubular cells ( Arg2 lox/lox /Pax8‐rtTA/LC1 or, cKO mice). Results 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 24 hours 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. Conclusion 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.