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.
Highlights
Aging is an important risk factor of chronic kidney disease (CKD) and is associated with significant structural and functional changes of the kidney in elderly individuals even in the absence of age-related comorbidities[1]
Renal aging is accompanied by the decline of total nephron size and number, global glomerulosclerosis, tubulointerstitial fibrosis involving TGFβ1 and collagen, arteriosclerosis, and inflammation cytokines[2,3]
We report that renal Arg-II expression is augmented in proximal tubular S3 segment cells with aging in a mouse model and ablation of Arg-II reduces renal inflammaging phenotypes mainly in the female mice
Summary
Aging is an important risk factor of chronic kidney disease (CKD) and is associated with significant structural and functional changes of the kidney in elderly individuals even in the absence of age-related comorbidities[1]. Renal aging is accompanied by the decline of total nephron size and number, global glomerulosclerosis, tubulointerstitial fibrosis involving TGFβ1 and collagen, arteriosclerosis, and inflammation cytokines[2,3]. Our understanding of the underlying mechanisms of renal aging is, incomplete. As the consequence of steady growth in the population of elderly people in our society, an increased incidence of CKD is predicted for the future[4]. Population-based studies indicate that CKD affects more women than men and women report a higher symptom burden and greater symptom severity than men[5,6]
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