Role of tubular epithelial arginase-II in renal inflammaging

Abstract

The aging kidney undergoes complex changes and is vulnerable to injury and development of chronic kidney disease (CKD) with preponderance affecting more women than men. Evidence has been presented that the type-II L-arginine:ureohydrolase, arginase-II (Arg-II) plays a role in the acceleration of aging. Arg-II is highly expressed in the kidney. However, the role of Arg-II in renal aging is not known. This study is to investigate whether Arg-II is involved in the kidney aging process dependently on sex. Arg-II level in the kidney of wild type (WT) mice is significantly elevated with aging, which is accompanied by an increase in expression of the inflammatory cytokines/chemokines, tissue macrophages, factors involved in fibrosis, and tubulointestitial fibrosis in both males and females. This renal aging phenotype is significantly suppressed in arg-II−/− mice, mainly in the females in which Arg-II level is higher than in the males. Importantly, numerous factors such as IL-1β, MCP1, VCAM-1, and TGFβ1 are mainly localized in the proximal tubular S3 segment cells expressing Arg-II in the aging kidney. In human proximal tubular cells (HK-2), TNF-α enhances adhesion molecule expression dependently on Arg-II upregulation. Overexpression of Arg-II in the cells enhances TGFβ1 levels which is prevented by mitochondrial ROS inhibition. In summary, our study reveals that renal proximal tubular Arg-II plays an important role in the kidney aging process in females. Arg-II could be a promising therapeutic target for the treatment and prevention of aging-associated kidney diseases.

Presentation_1.PPTX

“…Both protective and detrimental effects of Arg-II in renal damage are reported in mouse models in response to ischemia (Ansermet et al, 2020;Hara et al, 2020). Taken into account that the mitochondrial Arg-II and TGFβ1 are upregulated by hypoxia (Krotova et al, 2010;Prieto et al, 2011;Cowburn et al, 2016;Pandey et al, 2018;Liang et al, 2019) and over-expression of Arg-II in the HK2 cells causes mtROS generation and enhances TGFβ1 production (Huang et al, 2021), we hypothesize that hypoxia causes renal tubular cell damage through up-regulation of Arg-II-mtROS-TGFβ1 cascade.…”

“…Arg-II is a mitochondrial enzyme and is exclusively and highly expressed in the renal PTC straight segment (Huang et al, 2021). Emerging evidence indicates that upregulation of Arg-II plays a detrimental role in kidney of mouse models of ischemia and diabetes (Morris et al, 2011;Toque et al, 2013;You et al, 2013).…”

“…Mitochondrial superoxide generation was studied using MitoSox (Huang et al, 2021). The cells were incubated with MitoSox at the concentration of 5 µmol/L for 10 min.…”

“…It is interesting to note that the L-arginine-ureohydrolase type-II or arginase type-II (Arg-II) is prominently expressed in the renal PTC straight segment under physiological conditions, but it is also inducible under stress or pathological conditions Ming, 2013, 2014;Huang et al, 2021). The enzyme is localized in mitochondria and metabolizes L-arginine to L-ornithine and urea (Wu and Morris, 1998).…”

“…It is well known since long time that Arg-II is prominently expressed in the kidney (Miyanaka et al, 1998;Levillain et al, 2005;Choi et al, 2012). Investigation of the function of Arg-II in renal physiology and pathophysiology are just emerging in recent years and contradictory results have been reported in the literature (Huang et al, 2018(Huang et al, , 2021Ansermet et al, 2020;Hara et al, 2020). Both protective and detrimental effects of Arg-II in renal damage are reported in mouse models in response to ischemia (Ansermet et al, 2020;Hara et al, 2020).…”