The RAGE/STAT5/autophagy axis regulates senescence in mesangial cells.

Renal aging and associated functional decline are associated with an increase in cellular senescence. Previous studies show a direct correlation between advanced glycation end products (AGEs) accumulation and renal aging, chronic kidney disease (CKD) and other nephropathies, although the underlying molecular mechanisms remain largely unclear. We found elevated levels of the receptor of advanced glycation end product as well as in aged human kidneys, as well as in human mesangial cells aged artificially through AGEs. Furthermore, genetic and pharmacological ablation of duanyu18135 significantly downregulated p16 levels and the percentage of β-Gal-positive senescent cells in mesangial cells and kidneys of SD rats, indicating that AGEs-induced senescence depends on duanyu18135 signaling. The aged kidney tissues (both in patients and SD rats) and mesangial cells show low levels of LC3 (both LC3-II and LC3-II/I), and cultured mesangial cells also show fewer autolysosomes, autophagosomes, and autophagic vacuoles, which can be partially restored upon duanyu18135 inhibition. This indicates that AGEs accumulation also obliterates the protective effects of autophagy against aging via the axis. Direct inhibition of autophagy via 3-methyladenine (3-MA) increases the phenotype of renal aging without activating it is inhibition of autophagy caused by duanyu1648/duanyu18135 that leads to mesangial aging. In conclusion, we found AGEs induced inhibition of autophagy and cellular senescence in mesangial cells via the duanyu1648/duanyu18135 pathway. Moreover, we found that duanyu1648/duanyu18135 acts as a key link between autophagy and senescence in the process of mesangial aging in vivo and in vitro.

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