Genetic Targeting of Arginase-II in Mouse Prevents Renal Oxidative Stress and Inflammation in Diet-Induced Obesity

Abstract

Obesity is associated with development and progression of chronic kidney disease (CKD). Recent evidence demonstrates that enhanced levels of the L-arginine:ureahydrolase, including the two isoenzymes arginase-I (Arg-I) and arginase-II (Arg-II) in vascular endothelial cells promote uncoupling of endothelial nitric oxide synthase (eNOS), leading to increased superoxide radical anion and decreased NO production thereby endothelial dysfunction. Arg-II but not Arg-I is abundantly expressed in kidney and the role of Arg-II in CKD is uncertain and controversial. We aimed to investigate the role of Arg-II in renal damage associated with diet-induced obesity mouse model. Wild type (WT) C57BL/6 mice and mice deficient in Arg-II gene (Arg-II−/−) were fed with either a normal chow (NC) or a high-fat-diet (HFD) for 14 weeks (starting at the age of 7 weeks) to induce obesity. In WT mice, HFD feeding caused frequent renal lipid accumulation, enhancement of renal reactive oxygen species (ROS) levels which could be attenuated by a NOS inhibitor, suggesting uncoupling of NOS in kidney. HFD feeding also significantly augmented renal Arg-II expression and activity. All the alterations in the kidney under HFD feeding were reduced in Arg-II−/− mice. Moreover, mesangial expansion as analyzed by Periodic Acid Schiff (PAS) staining and renal expression of vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HFD-fed WT mouse assessed by immunoblotting were reduced in the HFD-fed Arg-II−/− mice, although there was no significant difference in body weight and renal weight/body weight ratio between the WT and Arg-II−/− mice. Thus, Arg-II expression/activity is enhanced in kidney of diet-induced obesity mice. Genetic targeting of Arg-II prevents renal damage associated with obesity, suggesting an important role of Arg-II in obesity-associated renal disease development.

Arginase‐II negatively regulates renal aquaporin‐2 and water reabsorption

“…This result indicates a negative regulation of AQP2 expression and membrane association by Arg-II. Arg-II was also found abundantly and was constitutively expressed in proximal tubules as shown by our previously published studies (10, 20), which was not changed upon WD ( Fig. 3 A ).…”

“…It is well documented that Arg-II is abundantly expressed in the kidney, mainly in the S3 segment of the proximal tubules (10, 21, 22). Here, we demonstrate that Arg-II is induced by the V 2 receptor agonist in cultured collecting duct principal cells and in mouse under WD conditions, which stimulate AVP release as a physiologic response.…”

“…We provide both in vitro and in vivo evidence that Arg-II in collecting duct cells is up-regulated by V 2 receptor activation in parallel with an increase in AQP2 levels, whereby Arg-II negatively regulates AQP2 expression and its membrane association, which functions as a fine-tuning mechanism of AVP-mediated water reabsorption in the kidney. It is well documented that Arg-II is abundantly expressed in the kidney, mainly in the S3 segment of the proximal tubules (10,21,22). Here, we demonstrate that Arg-II is induced by the V 2 receptor agonist in cultured collecting duct principal cells and in mouse under WD conditions, which stimulate AVP release as a physiologic response.…”

“…Arg-I is expressed most abundantly in the liver, where its primary function is the detoxification of ammonia via the urea cycle, whereas Arg-II is widely expressed in extrahepatic tissues, most abundantly in the kidney (7). Although enhanced Arg-II expression/activity has been reported in pathologic conditions to mediate renal injury by reducing the bioavailability of the vasodilator, NO, by competing with eNOS for the common substrate, L-arginine (8)(9)(10), the physiologic role of Arg-II in the kidney remains unknown. Herein, we provide the first evidence to our knowledge of a physiologic function of Arg-II in the negative regulation of AQP2 expression and function in the collecting ducts of the kidney.…”

Arginase-II Deficiency Extends Lifespan in Mice

“…These studies demonstrate that Arg-II plays a causative role in cellular senescence and in the organ functional decline. Previous studies including our own demonstrate beneficial effects of Arg-II deficiency in protection against development of cardiovascular diseases, insulin resistance, and diabetic complications (Ming et al, 2012 ; Yepuri et al, 2012 ; Huang et al, 2016 ; Xiong et al, 2017 ), which could contribute to the lifespan extension by Arg-II deficiency. It remains a great challenge to investigate which organ or cell and to which degree of the organ or cell contribute to the extension of lifespan.…”