Cellular senescence of renal tubular epithelial cells in acute kidney injury

Abstract

Cellular senescence represents an irreversible state of cell-cycle arrest during which cells secrete senescence-associated secretory phenotypes, including inflammatory factors and chemokines. Additionally, these cells exhibit an apoptotic resistance phenotype. Cellular senescence serves a pivotal role not only in embryonic development, tissue regeneration, and tumor suppression but also in the pathogenesis of age-related degenerative diseases, malignancies, metabolic diseases, and kidney diseases. The senescence of renal tubular epithelial cells (RTEC) constitutes a critical cellular event in the progression of acute kidney injury (AKI). RTEC senescence inhibits renal regeneration and repair processes and, concurrently, promotes the transition of AKI to chronic kidney disease via the senescence-associated secretory phenotype. The mechanisms underlying cellular senescence are multifaceted and include telomere shortening or damage, DNA damage, mitochondrial autophagy deficiency, cellular metabolic disorders, endoplasmic reticulum stress, and epigenetic regulation. Strategies aimed at inhibiting RTEC senescence, targeting the clearance of senescent RTEC, or promoting the apoptosis of senescent RTEC hold promise for enhancing the renal prognosis of AKI. This review primarily focuses on the characteristics and mechanisms of RTEC senescence, and the impact of intervening RTEC senescence on the prognosis of AKI, aiming to provide a foundation for understanding the pathogenesis and providing potentially effective approaches for AKI treatment.

Fig. 1. The phenotypes and markers of cellular senescence.

Cellular senescence is an irreversible state of cell-cycle arrest, which exhibits SASP and apoptotic resistance phenotypes. Senescent cells are enlarged and have an irregular shape. The phosphorylation of γH2AX increases following DNA damage in cellular senescence. SAHF accumulates and Lamin B1 downregulates in the nucleus of the senescent cell. Enhanced lysosomal content (SA-β-gal), ER stress, and mitochondrial dysfunction are observed in senescent cells. Moreover, lipid metabolism, glutamine catabolism, and NAD+ metabolism are abnormal after cellular senescence.

Fig. 2. Senescence interventions.

Inhibiting cell senescence, targeted clearance of senescent cells, promoting apoptosis of senescent cells, and inhibiting SASP release could be potential methods for improving renal prognosis following AKI.