Cellular Senescence of Renal Tubular Epithelial Cells in Acute Kidney Injury

Overview

Journal Cell Death Discov

Date 2024 Feb 5

PMID 38316761

Authors

Juan Chen

Huhai Zhang

Xiangling Yi

Qian Dou

Xin Yang

Yani He

Jia Chen

Kehong Chen

Affiliations

Soon will be listed here.

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.

Citing Articles

The Potential Role of Advanced Glycation End Products in the Development of Kidney Disease.

Ma Y, Wang X, Lin S, King L, Liu L Nutrients. 2025; 17(5).

PMID: 40077627 PMC: 11902189. DOI: 10.3390/nu17050758.

An adoptive cell therapy with TREM2-overexpressing macrophages mitigates the transition from acute kidney injury to chronic kidney disease.

Zhang Y, Liu Y, Luo S, Liang H, Guo C, Du Y Clin Transl Med. 2025; 15(3):e70252.

PMID: 40000418 PMC: 11859120. DOI: 10.1002/ctm2.70252.

Ankrd1 as a potential biomarker for the transition from acute kidney injury to chronic kidney disease.

Li H, Hu L, Zheng C, Kong Y, Liang M, Li Q Sci Rep. 2025; 15(1):4659.

PMID: 39920300 PMC: 11806044. DOI: 10.1038/s41598-025-88752-4.

Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injury.

Giuliani K, Nag P, Adams B, Wang X, Hong S, Grivei A Cell Death Dis. 2025; 16(1):61.

PMID: 39890773 PMC: 11785723. DOI: 10.1038/s41419-025-07386-6.

Xanthohumol attenuates TXNIP-mediated renal tubular injury in vitro and in vivo diabetic models.

Zhang Y, Pan R, Shou Z, Zhao Y J Nat Med. 2025; 79(2):314-327.

PMID: 39752106 DOI: 10.1007/s11418-024-01863-6.

References

Miwa S, Jow H, Baty K, Johnson A, Czapiewski R, Saretzki G . Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice. Nat Commun. 2014; 5:3837. PMC: 4024759. DOI: 10.1038/ncomms4837. View

Yuan Y, Zheng Y, Zhang X, Chen Y, Wu X, Wu J . BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of PARK2. Autophagy. 2017; 13(10):1754-1766. PMC: 5640199. DOI: 10.1080/15548627.2017.1357792. View

Jin H, Zhang Y, Ding Q, Wang S, Rastogi P, Dai D . Epithelial innate immunity mediates tubular cell senescence after kidney injury. JCI Insight. 2019; 4(2). PMC: 6413792. DOI: 10.1172/jci.insight.125490. View

Strzyz P . Bend it like glycocalyx. Nat Rev Mol Cell Biol. 2019; 20(7):388. DOI: 10.1038/s41580-019-0142-2. View

Liu J, Yang J, Chen X, Cai G, Lin L, He Y . Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy. Am J Physiol Cell Physiol. 2015; 308(8):C621-30. DOI: 10.1152/ajpcell.00096.2014. View

Bechtel W, McGoohan S, Zeisberg E, Muller G, Kalbacher H, Salant D . Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med. 2010; 16(5):544-50. PMC: 3106179. DOI: 10.1038/nm.2135. View

Liu B, Tang T, Lv L, Lan H . Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int. 2018; 93(3):568-579. DOI: 10.1016/j.kint.2017.09.033. View

Leidal A, Levine B, Debnath J . Autophagy and the cell biology of age-related disease. Nat Cell Biol. 2018; 20(12):1338-1348. DOI: 10.1038/s41556-018-0235-8. View

Sharpless N, Sherr C . Forging a signature of in vivo senescence. Nat Rev Cancer. 2015; 15(7):397-408. DOI: 10.1038/nrc3960. View

10.

Deolal P, Mishra K . Regulation of diverse nuclear shapes: pathways working independently, together. Commun Integr Biol. 2021; 14(1):158-175. PMC: 8259725. DOI: 10.1080/19420889.2021.1939942. View

11.

Farr J, Khosla S . Cellular senescence in bone. Bone. 2019; 121:121-133. PMC: 6485943. DOI: 10.1016/j.bone.2019.01.015. View

12.

Davaapil H, Brockes J, Yun M . Conserved and novel functions of programmed cellular senescence during vertebrate development. Development. 2016; 144(1):106-114. PMC: 5278627. DOI: 10.1242/dev.138222. View

13.

Bourdens M, Jeanson Y, Taurand M, Juin N, Carriere A, Clement F . Short exposure to cold atmospheric plasma induces senescence in human skin fibroblasts and adipose mesenchymal stromal cells. Sci Rep. 2019; 9(1):8671. PMC: 6572822. DOI: 10.1038/s41598-019-45191-2. View

14.

Gerhardt L, Liu J, Koppitch K, Cippa P, McMahon A . Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury. Proc Natl Acad Sci U S A. 2021; 118(27). PMC: 8271768. DOI: 10.1073/pnas.2026684118. View

15.

Turgeon M, Perry N, Poulogiannis G . DNA Damage, Repair, and Cancer Metabolism. Front Oncol. 2018; 8:15. PMC: 5807667. DOI: 10.3389/fonc.2018.00015. View

16.

Shmulevich R, Krizhanovsky V . Cell Senescence, DNA Damage, and Metabolism. Antioxid Redox Signal. 2020; 34(4):324-334. DOI: 10.1089/ars.2020.8043. View

17.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

18.

Moiseeva O, Deschenes-Simard X, St-Germain E, Igelmann S, Huot G, Cadar A . Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell. 2013; 12(3):489-98. DOI: 10.1111/acel.12075. View

19.

Westhoff J, Schildhorn C, Jacobi C, Homme M, Hartner A, Braun H . Telomere shortening reduces regenerative capacity after acute kidney injury. J Am Soc Nephrol. 2009; 21(2):327-36. PMC: 2834551. DOI: 10.1681/ASN.2009010072. View

20.

Bao H, Cao J, Chen M, Chen M, Chen W, Chen X . Biomarkers of aging. Sci China Life Sci. 2023; 66(5):893-1066. PMC: 10115486. DOI: 10.1007/s11427-023-2305-0. View