PAR2‐mediated cellular senescence promotes inflammation and fibrosis in aging and chronic kidney disease

Author:

Ha Sugyeong1,Kim Hyun Woo1,Kim Kyung Mok1,Kim Byeong Moo1,Kim Jeongwon1,Son Minjung1,Kim Doyeon1,Kim Mi‐Jeong1,Yoo Jian1,Yu Hak Sun2,Jung Young‐Suk1,Lee Jaewon1,Chung Hae Young1ORCID,Chung Ki Wung1ORCID

Affiliation:

1. Department of Pharmacy and Research Institute for Drug Development, College of Pharmacy Pusan National University Busan Korea

2. Department of Parasitology and Tropical Medicine, School of Medicine Pusan National University Yangsan Korea

Abstract

AbstractCellular senescence contributes to inflammatory kidney disease via the secretion of inflammatory and profibrotic factors. Protease‐activating receptor 2 (PAR2) is a key regulator of inflammation in kidney diseases. However, the relationship between PAR2 and cellular senescence in kidney disease has not yet been described. In this study, we found that PAR2‐mediated metabolic changes in renal tubular epithelial cells induced cellular senescence and increased inflammatory responses. Using an aging and renal injury model, PAR2 expression was shown to be associated with cellular senescence. Under in vitro conditions in NRK52E cells, PAR2 activation induces tubular epithelial cell senescence and senescent cells showed defective fatty acid oxidation (FAO). Cpt1α inhibition showed similar senescent phenotype in the cells, implicating the important role of defective FAO in senescence. Finally, we subjected mice lacking PAR2 to aging and renal injury. PAR2‐deficient kidneys are protected from adenine‐ and cisplatin‐induced renal fibrosis and injury, respectively, by reducing senescence and inflammation. Moreover, kidneys lacking PAR2 exhibited reduced numbers of senescent cells and inflammation during aging. These findings offer fresh insights into the mechanisms underlying renal senescence and indicate that targeting PAR2 or FAO may be a promising therapeutic approach for managing kidney injury.

Funder

National Research Foundation of Korea

Publisher

Wiley

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