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.
Highlights
According to the latest Non-Communicable Diseases RiskFactor Collaboration (NCD-RisC) report, in 2014 there were 422 million people worldwide who had diabetes, i.e., roughly a four-fold increase over the past 35 years (Collaboration, 2016)
The mechanisms underlying obesity-associated diabetic renal damage are complex and have not yet been fully understood, it has been demonstrated that ectopic renal lipid accumulation, inflammation including macrophage infiltration in kidney through adhesion molecules, i.e., vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule1 (ICAM-1), glomerulus mesangial expansion, impaired endothelial nitric oxide (NO) bioavailability and oxidative stress or increased reactive oxygen species (ROS) generation in kidney are importantly involved in the development of diabetic renal damage (Nakagawa et al, 2011)
Confocal microscopic immunofluorescence staining showed that ArgII was mainly expressed in tubules of outer medulla, which is increased in the HFD fed Wild type (WT) mice (Figure 2)
Summary
According to the latest Non-Communicable Diseases RiskFactor Collaboration (NCD-RisC) report, in 2014 there were 422 million people worldwide who had diabetes, i.e., roughly a four-fold increase over the past 35 years (Collaboration, 2016). Under eNOS-uncoupling condition, superoxide radical anion reacts with NO, resulting in decreased NO bioavailability and increased generation of the more potent pro-oxidant peroxynitrite causing nitrosative stress (Förstermann and Sessa, 2012). NO is derived from L-arginine and decrease in NO is important for pathogenesis of vascular complications and for progression of renal disease associated with diabetes (Cheng and Harris, 2014). Among other mechanisms, elevated activity and/or expression of arginase i.e., the L-arginine:ureahydrolase including arginase-I (Arg-I) and arginase-II (Arg–II) isoenzyme, has been shown to cause eNOSuncoupling, resulting in increased oxidative stress in aging and age-associated cardiovascular diseases including atherosclerosis and type 2 diabetic vascular dysfunctions (Yepuri et al, 2012; Li and Förstermann, 2013)
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