1. Academic Validation
  2. PAR2-mediated cellular senescence promotes inflammation and fibrosis in aging and chronic kidney disease

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

  • Aging Cell. 2024 Apr 30:e14184. doi: 10.1111/acel.14184.
Sugyeong Ha 1 Hyun Woo Kim 1 Kyung Mok Kim 1 Byeong Moo Kim 1 Jeongwon Kim 1 Minjung Son 1 Doyeon Kim 1 Mi-Jeong Kim 1 Jian Yoo 1 Hak Sun Yu 2 Young-Suk Jung 1 Jaewon Lee 1 Hae Young Chung 1 Ki Wung Chung 1
Affiliations

Affiliations

  • 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

Cellular 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.

Keywords

PAR2; SASP; aging; fatty acid oxidation; fibrosis; inflammation; senescence.

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