2.2.9. Cellular Senescence

Cellular senescence appears to play an important role in the pathogenesis of CKD [76,77]. The accumulation of senescent cells may be responsible for insufficient repair capacity and functional loss. Senescent cells accumulate in the renal parenchyma, leading to tissue deterioration, fibrosis, and aberrant signaling in different types of cell populations [29,69,78]. Senescent cells of renal system express several markers, such as cell cycle arrest proteins of G1/S and G2/M checkpoints such as p16INK4A, p21WAF/CIP1, p27KIP1, and p53, but they do not express proliferation markers such as Ki67 [79–81]. Interestingly, selective ablation of senescent (p16INK4a-positive) cells in transgenic mice is linked to diminished expression of TNF-α, IL-6, and IL-1α in many tissues, including the kidney [79]. Cellular senescence has been linked to telomere shortening [82], which upregulates a DNA damage response and activates phosphatidylinositol 3 kinase-like kinases and Rad3-related kinases that lead to p53 activation. Active p53 upregulates transcription of pro-apoptotic genes and/or genes that inhibit cyclin-dependent kinase (i.e., p21cip1/waf1). Activation of p21cip/waf1 may cause permanent cell cycle arrest [62,80].

Importantly, senescent cells have a specific secretome-defined, senescence-associated secretory phenotype (SASP), which includes a broad range of pro-inflammatory cytokines, chemokines, growth factors, and matrix-degrading factors (e.g., IL-6, IL-1α, IL-1β, chemokine ligand 1 (GROα; CXCL1), connective tissue growth factor (CTGF), plasminogen activator inhibitor 1 (PAI-1), C-C motif chemokine 2 (CCL2)) [79,80,83]. Recent studies report that the expression of integrin β3 increased significantly in senescent cells, which led to the activation of p53 and the secretion of TGF-β [84]. These molecules and others, such as TNFα, IL-6, and monocyte chemoattractant protein 1 (MCP-1), can promote an inflammatory microenvironment and might be important drivers of inflammation-related injury and enhance progression of CKD [83,85].
