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Background and Aims Acute kidney injury (AKI) is associated with elevated mortality and morbidity presenting higher frequency in aged patients. Different mechanisms are activated in AKI, including tubular epithelial cell death (apoptosis and regulated necrosis), inflammatory cell infiltration, impaired mitochondrial function, and prolonged cell-cycle arrest (or cellular senescence). There is a strong connection between pathways activated in AKI and development of cellular senescence, a process implicated in regeneration failure and progression to fibrosis. However, the molecular mechanisms in ageing-associated mortality are not completely understood. Our aim was to investigate age-related molecular mechanisms of AKI. Method Experimental nephropathy by folic acid administration (FA, 125mg/kg) was induced in young (3 months) and old (12 months) mice. Renal lesions and mechanisms were evaluated at 48 hours (AKI acute phase). Results AKI mortality was higher in old (50 %) than in young (15%) mice 4 days after FA injection (pilot study). Tubular damage score (PAS evaluation) and KIM-1 tubular expression (renal damage biomarker) were also higher in old than in young FA-injected mice after 48h. The number of infiltrating immune cells (mainly neutrophils and macrophages) and gene expression levels of proinflammatory genes (Lcn-2 and ccl2) were significantly higher in FA kidneys of old as compared to young mice. Regulated necrosis (necroptosis), contrary to apoptosis, induces an inflammatory response and necroinflammation, being macrophages the key effector immune cells of this cell death pathway. Among some of the key necroptosis mediators, MLKL and RIPK3 were higher in old FA kidneys. These data could indicate a magnification of the inflammatory response to AKI in older mice. In contrast, expression of protective factors was dramatically downregulated in old FA mice, including the mitochondrial biogenesis driver PGC-1α, and the antiaging factor Klotho. Cellular senescence was induced in FA kidneys, as indicated by increased levels of cyclin-dependent kinase inhibitors p16ink4a and p21cip1, and of the DNA Damage Response marker yH2AX. Importantly, p21 mRNA expression and nuclear staining for p21 and yH2AX were increased in FA kidneys, and the fold increase was significantly higher in old than in young mice. Also, the expression of senescence-associated secretory phenotype (SASP) components (Tgfb1, Il-6, and Serpine-1) was significantly higher in old FA mouse kidneys. Interestingly, also some infiltrating immune cells were p21/yH2AX positive, suggesting molecular senescence in the immune cells (“immunesenescence”) and inflammation in the ageing kidney (“inflammaging”) are involved in the aggravated AKI response to FA in old mice. Conclusion Our data indicate that in advanced age, exposure to toxic compounds results in a more severe AKI response that might relate to an early inflammatory response characterize by more extensive necroptosis and activation of pathways related to cellular senescence of resident kidney cells and infiltrating inflammatory cells.

MO338INCREASED INFLAMMATORY RESPONSE IS A HALLMARK OF AGE-RELATED AGGRAVATION OF EXPERIMENTAL AKI