#3612 STING IS INVOLVED IN THE CELLULAR SENESCENCE PROCESS ASSOCIATED WITH RENAL AGING

Abstract

Abstract Background and Aims Cellular senescence is an adaptative process in response to damage or stress. It consists of a cell-cycle-arrest (CCA) alternatively to the programmed cell death process, which is necessary for the regeneration of damaged tissues. However, permanent senescence promotes an aberrant inflammatory response associated to chronic diseases, fibrosis and aging. One of the mechanisms which triggers cellular senescence is the DNA damage response (DDR) activation, that leads to the emergence of a cellular senescence-associated secretory phenotype (SASP), inflammation and fibrosis. Sting is a detection protein of pathogenic DNA derived from cellular damage and genotoxic and environmental stresses, starting an innate immune response and inflammation. A deregulated DDR response and thus the process of senescence itself, are also able to activate Sting. Nevertheless, the role of Sting in senescence associated to renal aging is an unknown fact. The aim of this study is to evaluate the role of STING in aging-associated pathophysiological changes in the kidney. Method Studies were carried out in C57BL76 mice (wild type mice) and in mice with a phenotype deficient in the Sting gene (KO-Sting), of different ages: 3 (young) and 18 (aged) months. Renal function parameters, histology and markers of kidney damage, and activation of cellular senescence in presence or absence of Sting were studied. Results C57BL76 mice of 18 month presented renal dysfunction and fibrosis that was not observed in KO-Sting mice of the same age. Interestingly, 18 months wild-type mice showed an activation of the Sting pathway, characterized by increased transcriptional levels of Ifit1, Oasl2, Usp19 and Mx2. Moreover, the activation of STING pathway was associated to activation of cellular senescence mechanisms, including elevated renal gene expression of SASP components, such as Ccl2, Ccn2, Il1β, Il6, Pai1 or Tgf-β. Importantly, in Sting KO mice of 18 months, DNA damage response was not activated (no increase in ɣH2AX) and cell cycle arrest was not induced, as determined by the p21 and p16 markers. In addition, SAPS gene expression remained at basal levels in aged KO-Sting mice. However, Klotho gene expression levels are downregulated in all 18-month-old mice, wild type and KO mice. Conclusion In conclusion, these findings suggest that the absence of STING prevents age-related renal cellular senescence in a Klotho independent manner in a murine experimental model.