Cellular Senescence in the Aging Kidney
Much of past research into age-related disease involves looking at changes in gene expression in the diseased organ, a very low-level laundry list of alterations. This is somewhat decoupled from the approach of looking at changes in cell behavior, a high-level laundry list of alterations. A sizable fraction of life science research involves trying to make firm connections between these two sets of data, to better steer development efforts towards interfering in more relevant rather than less relevant mechanisms. Here, as an example of this sort of work, researchers link PAR2 expression in the kidney to cellular senescence in that organ. Senescent cells accumulate with age to produce chronic inflammation and other tissue dysfunction. There is considerable interest in finding ways to both selectively remove these cells, or prevent their creation in the first place.
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 a kidney epithelial cell line, 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.
https://pubmed.ncbi.nlm.nih.gov/34318973
Results: Expression levels of ageing marker genes (p21, p16 and p53) and senescence-associated secretory phenotypes of the kidney were increased in the vehicle-treated db/db (db/db + vehicle) group compared with the db/+ group, and this increase was markedly reversed in the dapagliflozin-treated db/db (db/db + SGLT2 inhibitor) group, but not in the glimepiride-treated db/db (db/db + sulphonylurea [SU]) group. In the kidneys of mice in the db/db + SGLT2 inhibitor group, oxidative stress and DNA damage were also reduced compared with those of mice in the db/db + vehicle and db/db + SU groups. Dapagliflozin increased plasma β-HB, which reduced H2 O2 -induced DNA damage and senescence in HK-2 cells. β-HB-induced NRF2 nuclear translocation mediated anti-senescent effects by inducing antioxidant pathways.
Conclusions: Dapagliflozin prevented the progression of diabetic kidney disease by inhibiting cellular senescence and oxidative stress via ketone-induced NRF2 activation.