Abstract
Acute kidney injury (AKI) is more frequent in elderly patients. Mechanisms contributing to AKI (tubular cell death, inflammatory cell infiltration, impaired mitochondrial function, and prolonged cell-cycle arrest) have been linked to cellular senescence, a process implicated in regeneration failure and progression to fibrosis. However, the molecular and pathological basis of the age-related increase in AKI incidence is not completely understood. To explore these mechanisms, experimental AKI was induced by folic acid (FA) administration in young (3-months-old) and old (1-year-old) mice, and kidneys were evaluated in the early phase of AKI, at 48 h. Tubular damage score, KIM-1 expression, the recruitment of infiltrating immune cells (mainly neutrophils and macrophages) and proinflammatory gene expression were higher in AKI kidneys of old than of young mice. Tubular cell death in FA-AKI involves several pathways, such as regulated necrosis and apoptosis. Ferroptosis and necroptosis cell-death pathways were upregulated in old AKI kidneys. In contrast, caspase-3 activation was only found in young but not in old mice. Moreover, the antiapoptotic factor BCL-xL was significantly overexpressed in old, injured kidneys, suggesting an age-related apoptosis suppression. AKI kidneys displayed evidence of cellular senescence, such as increased levels of cyclin dependent kinase inhibitors p16ink4a and p21cip1, and of the DNA damage response marker γH2AX. Furthermore, p21cip1 mRNA expression and nuclear staining for p21cip1 and γH2AX were higher in old than in young FA-AKI mice, as well as the expression of senescence-associated secretory phenotype (SASP) components (Il-6, Tgfb1, Ctgf, and Serpine1). Interestingly, some infiltrating immune cells were p21 or γH2AX positive, suggesting that molecular senescence in the immune cells (“immunosenescence”) are involved in the increased severity of AKI in old mice. In contrast, expression of renal protective factors was dramatically downregulated in old AKI mice, including the antiaging factor Klotho and the mitochondrial biogenesis driver PGC-1α. In conclusion, aging resulted in more severe AKI after the exposure to toxic compounds. This increased toxicity may be related to magnification of proinflammatory-related pathways in older mice, including a switch to a proinflammatory cell death (necroptosis) instead of apoptosis, and overactivation of cellular senescence of resident renal cells and infiltrating inflammatory cells.
Highlights
Acute kidney injury (AKI) is a common and devastating pathologic condition in part due its higher incidence in the elderly and its association with an increased short- and longterm mortality (Levey and James, 2017; Hounkpatin et al, 2019; Martin-Cleary et al, 2019; Logan et al, 2020)
The observations regarding the mechanisms triggered by AKI point to an agerelated magnification of several proinflammatory-related processes, including gene overexpression of some proinflammatory factors (Lcn-2, Cxcl1, and Il-6), overactivation of inflammatory-cell-death pathways such as necroptosis, and amplification of cellular senescence including immunosenescence (Figure 10)
After an ischemic or nephrotoxic AKI insult, a wide range of pathophysiological events occur, including changes in tubular cell phenotypes, such as loss of physical cell–cell interactions and partial epithelial-to-mesenchymal transition (EMT) (RuizOrtega et al, 2020), or even tubular cell death mediated by apoptosis and prominent programmed and unprogrammed necrosis (Martin-Sanchez et al, 2018b; Martin-Sanchez et al, 2018a)
Summary
Acute kidney injury (AKI) is a common and devastating pathologic condition in part due its higher incidence in the elderly and its association with an increased short- and longterm mortality (Levey and James, 2017; Hounkpatin et al, 2019; Martin-Cleary et al, 2019; Logan et al, 2020). AKI is closely related to chronic kidney disease (CKD) as AKI may accelerate CKD progression to end-stage renal disease (ESRD) and CKD predisposes to AKI (Venkatachalam et al, 2015; Siew et al, 2016; Ruiz-Ortega et al, 2020). All these facts underscore the importance of the research in this area. Targeting ferroptosis by chemical inhibition or gene expression modulation reduced tubular injury and improved renal function in different experimental models, including IRI and FA-AKI (Martin-Sanchez et al, 2017; Martin-Sanchez et al, 2020)
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