Research progress on renal tubular cell senescence in acute kidney injury_West China Medical Journal

Authors：

CHEN Jia ,  HE Yani

Department of Nephrology, Daping Hospital (Army Medical Center), Army Medical University, Chongqing 400038, P. R. China;

Corresponding author：

HE Yani, Email: heynmail@163.com

Keywords：

Renal tubular cell; cell senescence; acute kidney injury

DOI：

10.7507/1002-0179.202206040

Video：

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Abstract Full text Figures/Tables Video References Cited by

Cell senescence is a state of irreversible cell cycle arrest and simultaneously secretes inflammatory factors, chemokines and other senescence-associated secretory phenotype (SASP), which plays an important role in the progression of kidney diseases, metabolic diseases and other diseases. Renal tubular cell (RTC) senescence is a key cellular biological event in the progression of acute kidney injury (AKI). Senescent RTCs not only inhibit the regeneration and repair of AKI, but also release SASP to promote the progression of AKI. Inhibition of RTC senescence, targeted removal of senescent RTCs or promotion of senescent RTCs apoptosis could improve the prognosis of AKI, indicating that these methods have broad application prospects.

Citation： CHEN Jia, HE Yani. Research progress on renal tubular cell senescence in acute kidney injury. West China Medical Journal, 2022, 37(7): 1076-1080. doi: 10.7507/1002-0179.202206040 Copy

1.	Yang L, Xing G, Wang L, et al. Acute kidney injury in China: a cross-sectional survey. Lancet, 2015, 386(10002): 1465-1471.
2.	Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet, 2019, 394(10212): 1949-1964.
3.	Lin X, Jin H, Chai Y, et al. Cellular senescence and acute kidney injury. Pediatr Nephrol, 2022.
4.	Li Y, Lerman LO. Cellular senescence: a new player in kidney injury. Hypertension, 2020, 76(4): 1069-1075.
5.	Docherty MH, O’Sullivan ED, Bonventre JV, et al. Cellular senescence in the kidney. J Am Soc Nephrol, 2019, 30(5): 726-736.
6.	Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol, 2018, 28(6): 436-453.
7.	Wiley CD, Campisi J. The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat Metab, 2021, 3(10): 1290-1301.
8.	Muñoz-Espín D, Cañamero M, Maraver A, et al. Programmed cell senescence during mammalian embryonic development. Cell, 2013, 155(5): 1104-1118.
9.	Demaria M, Ohtani N, Youssef SA, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell, 2014, 31(6): 722-733.
10.	Sturmlechner I, Durik M, Sieben CJ, et al. Cellular senescence in renal ageing and disease. Nat Rev Nephrol, 2017, 13(2): 77-89.
11.	Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest, 2018, 128(4): 1238-1246.
12.	Sis B, Tasanarong A, Khoshjou F, et al. Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease. Kidney Int, 2007, 71(3): 218-226.
13.	Liu J, Yang JR, He YN, et al. Accelerated senescence of renal tubular epithelial cells is associated with disease progression of patients with immunoglobulin A (IgA) nephropathy. Transl Res, 2012, 159(6): 454-463.
14.	Satriano J, Mansoury H, Deng A, et al. Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes. Am J Physiol Cell Physiol, 2010, 299(2): C374-380.
15.	Luo C, Zhou S, Zhou Z, et al. Wnt9a promotes renal fibrosis by accelerating cellular senescence in tubular epithelial cells. J Am Soc Nephrol, 2018, 29(4): 1238-1256.
16.	Liu J, Huang K, Cai GY, et al. Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling. Cell Signal, 2014, 26(1): 110-121.
17.	Braun H, Schmidt BM, Raiss M, et al. Cellular senescence limits regenerative capacity and allograft survival. J Am Soc Nephrol, 2012, 23(9): 1467-1473.
18.	Stenvinkel P, Larsson TE. Chronic kidney disease: a clinical model of premature aging. Am J Kidney Dis, 2013, 62(2): 339-351.
19.	Yang L, Besschetnova TY, Brooks CR, et al. Epithelial cell cycle arrest in G₂/M mediates kidney fibrosis after injury. Nat Med, 2010, 16(5): 535-543.
20.	Yu SM, Bonventre JV. Acute kidney injury and maladaptive tubular repair leading to renal fibrosis. Curr Opin Nephrol Hypertens, 2020, 29(3): 310-318.
21.	Gerhardt LMS, Liu J, Koppitch K, et al. 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): e2026684118.
22.	Gorgoulis V, Adams PD, Alimonti A, et al. Cellular senescence: defining a path forward. Cell, 2019, 179(4): 813-827.
23.	Lee DH, Wolstein JM, Pudasaini B, et al. INK4a deletion results in improved kidney regeneration and decreased capillary rarefaction after ischemia-reperfusion injury. Am J Physiol Renal Physiol, 2012, 302(1): F183-F191.
24.	Jin H, Zhang Y, Ding Q, et al. Epithelial innate immunity mediates tubular cell senescence after kidney injury. JCI Insight, 2019, 4(2): e125490.
25.	Kim SR, Puranik AS, Jiang K, et al. Progressive cellular senescence mediates renal dysfunction in ischemic nephropathy. J Am Soc Nephrol, 2021, 32(8): 1987-2004.
26.	Jiang X, Ruan XL, Xue YX, et al. Metformin reduces the senescence of renal tubular epithelial cells in diabetic nephropathy via the MBNL1/miR-130a-3p/STAT3 pathway. Oxid Med Cell Longev, 2020, 2020: 8708236.
27.	Lee SH, Lee JH, Lee HY, et al. Sirtuin signaling in cellular senescence and aging. BMB Rep, 2019, 52(1): 24-34.
28.	Mogi M. Effect of renin-angiotensin system on senescence. Geriatr Gerontol Int, 2020, 20(6): 520-525.
29.	Megyesi J, Safirstein RL, Price PM. Induction of p21WAF1/CIP1/SDI1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure. J Clin Invest, 1998, 101(4): 777-782.
30.	Megyesi J, Andrade L, Vieira JM, et al. Positive effect of the induction of p21WAF1/CIP1 on the course of ischemic acute renal failure. Kidney Int, 2001, 60(6): 2164-2172.
31.	Wolstein JM, Lee DH, Michaud J, et al. INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction. Am J Physiol Renal Physiol, 2010, 299(6): F1486-F1495.
32.	Aldouahji M, Brugarolas J, Brown PA, et al. The cyclin kinase inhibitor p21WAF1/CIP1 is required for glomerular hypertrophy in experimental diabetic nephropathy. Kidney Int, 1999, 56(5): 1691-1699.
33.	Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 2011, 479(7372): 232-236.
34.	Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16 (Ink4a)-positive cells shorten healthy lifespan. Nature, 2016, 530(7589): 184-189.
35.	Chen Z, Yu J, Fu M, et al. Dipeptidyl peptidase-4 inhibition improves endothelial senescence by activating AMPK/SIRT1/Nrf2 signaling pathway. Biochem Pharmacol, 2020, 177: 113951.
36.	Kim KM, Noh JH, Bodogai M, et al. Identification of senescent cell surface targetable protein DPP4. Genes Dev, 2017, 31(15): 1529-1534.
37.	Sagiv A, Biran A, Yon M, et al. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene, 2013, 32(15): 1971-1977.
38.	Jia C, Ke-Hong C, Fei X, et al. Decoy receptor 2 mediation of the senescent phenotype of tubular cells by interacting with peroxiredoxin 1 presents a novel mechanism of renal fibrosis in diabetic nephropathy. Kidney Int, 2020, 98(3): 645-662.
39.	Chang J, Wang Y, Shao L, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med, 2016, 22(1): 78-83.
40.	Yosef R, Pilpel N, Tokarsky-Amiel R, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun, 2016, 7: 11190.
41.	Baar MP, Brandt RMC, Putavet DA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 2017, 169(1): 132-147.
42.	Chen J, Chen KH, Wang LM, et al. Decoy receptor 2 mediates the apoptosis-resistant phenotype of senescent renal tubular cells and accelerates renal fibrosis in diabetic nephropathy. Cell Death Dis, 2022, 13(6): 522.

1. Yang L, Xing G, Wang L, et al. Acute kidney injury in China: a cross-sectional survey. Lancet, 2015, 386(10002): 1465-1471.
2. Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet, 2019, 394(10212): 1949-1964.
3. Lin X, Jin H, Chai Y, et al. Cellular senescence and acute kidney injury. Pediatr Nephrol, 2022.
4. Li Y, Lerman LO. Cellular senescence: a new player in kidney injury. Hypertension, 2020, 76(4): 1069-1075.
5. Docherty MH, O’Sullivan ED, Bonventre JV, et al. Cellular senescence in the kidney. J Am Soc Nephrol, 2019, 30(5): 726-736.
6. Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol, 2018, 28(6): 436-453.
7. Wiley CD, Campisi J. The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat Metab, 2021, 3(10): 1290-1301.
8. Muñoz-Espín D, Cañamero M, Maraver A, et al. Programmed cell senescence during mammalian embryonic development. Cell, 2013, 155(5): 1104-1118.
9. Demaria M, Ohtani N, Youssef SA, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell, 2014, 31(6): 722-733.
10. Sturmlechner I, Durik M, Sieben CJ, et al. Cellular senescence in renal ageing and disease. Nat Rev Nephrol, 2017, 13(2): 77-89.
11. Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest, 2018, 128(4): 1238-1246.
12. Sis B, Tasanarong A, Khoshjou F, et al. Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease. Kidney Int, 2007, 71(3): 218-226.
13. Liu J, Yang JR, He YN, et al. Accelerated senescence of renal tubular epithelial cells is associated with disease progression of patients with immunoglobulin A (IgA) nephropathy. Transl Res, 2012, 159(6): 454-463.
14. Satriano J, Mansoury H, Deng A, et al. Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes. Am J Physiol Cell Physiol, 2010, 299(2): C374-380.
15. Luo C, Zhou S, Zhou Z, et al. Wnt9a promotes renal fibrosis by accelerating cellular senescence in tubular epithelial cells. J Am Soc Nephrol, 2018, 29(4): 1238-1256.
16. Liu J, Huang K, Cai GY, et al. Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling. Cell Signal, 2014, 26(1): 110-121.
17. Braun H, Schmidt BM, Raiss M, et al. Cellular senescence limits regenerative capacity and allograft survival. J Am Soc Nephrol, 2012, 23(9): 1467-1473.
18. Stenvinkel P, Larsson TE. Chronic kidney disease: a clinical model of premature aging. Am J Kidney Dis, 2013, 62(2): 339-351.
19. Yang L, Besschetnova TY, Brooks CR, et al. Epithelial cell cycle arrest in G₂/M mediates kidney fibrosis after injury. Nat Med, 2010, 16(5): 535-543.
20. Yu SM, Bonventre JV. Acute kidney injury and maladaptive tubular repair leading to renal fibrosis. Curr Opin Nephrol Hypertens, 2020, 29(3): 310-318.
21. Gerhardt LMS, Liu J, Koppitch K, et al. 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): e2026684118.
22. Gorgoulis V, Adams PD, Alimonti A, et al. Cellular senescence: defining a path forward. Cell, 2019, 179(4): 813-827.
23. Lee DH, Wolstein JM, Pudasaini B, et al. INK4a deletion results in improved kidney regeneration and decreased capillary rarefaction after ischemia-reperfusion injury. Am J Physiol Renal Physiol, 2012, 302(1): F183-F191.
24. Jin H, Zhang Y, Ding Q, et al. Epithelial innate immunity mediates tubular cell senescence after kidney injury. JCI Insight, 2019, 4(2): e125490.
25. Kim SR, Puranik AS, Jiang K, et al. Progressive cellular senescence mediates renal dysfunction in ischemic nephropathy. J Am Soc Nephrol, 2021, 32(8): 1987-2004.
26. Jiang X, Ruan XL, Xue YX, et al. Metformin reduces the senescence of renal tubular epithelial cells in diabetic nephropathy via the MBNL1/miR-130a-3p/STAT3 pathway. Oxid Med Cell Longev, 2020, 2020: 8708236.
27. Lee SH, Lee JH, Lee HY, et al. Sirtuin signaling in cellular senescence and aging. BMB Rep, 2019, 52(1): 24-34.
28. Mogi M. Effect of renin-angiotensin system on senescence. Geriatr Gerontol Int, 2020, 20(6): 520-525.
29. Megyesi J, Safirstein RL, Price PM. Induction of p21WAF1/CIP1/SDI1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure. J Clin Invest, 1998, 101(4): 777-782.
30. Megyesi J, Andrade L, Vieira JM, et al. Positive effect of the induction of p21WAF1/CIP1 on the course of ischemic acute renal failure. Kidney Int, 2001, 60(6): 2164-2172.
31. Wolstein JM, Lee DH, Michaud J, et al. INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction. Am J Physiol Renal Physiol, 2010, 299(6): F1486-F1495.
32. Aldouahji M, Brugarolas J, Brown PA, et al. The cyclin kinase inhibitor p21WAF1/CIP1 is required for glomerular hypertrophy in experimental diabetic nephropathy. Kidney Int, 1999, 56(5): 1691-1699.
33. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 2011, 479(7372): 232-236.
34. Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16 (Ink4a)-positive cells shorten healthy lifespan. Nature, 2016, 530(7589): 184-189.
35. Chen Z, Yu J, Fu M, et al. Dipeptidyl peptidase-4 inhibition improves endothelial senescence by activating AMPK/SIRT1/Nrf2 signaling pathway. Biochem Pharmacol, 2020, 177: 113951.
36. Kim KM, Noh JH, Bodogai M, et al. Identification of senescent cell surface targetable protein DPP4. Genes Dev, 2017, 31(15): 1529-1534.
37. Sagiv A, Biran A, Yon M, et al. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene, 2013, 32(15): 1971-1977.
38. Jia C, Ke-Hong C, Fei X, et al. Decoy receptor 2 mediation of the senescent phenotype of tubular cells by interacting with peroxiredoxin 1 presents a novel mechanism of renal fibrosis in diabetic nephropathy. Kidney Int, 2020, 98(3): 645-662.
39. Chang J, Wang Y, Shao L, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med, 2016, 22(1): 78-83.
40. Yosef R, Pilpel N, Tokarsky-Amiel R, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun, 2016, 7: 11190.
41. Baar MP, Brandt RMC, Putavet DA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 2017, 169(1): 132-147.
42. Chen J, Chen KH, Wang LM, et al. Decoy receptor 2 mediates the apoptosis-resistant phenotype of senescent renal tubular cells and accelerates renal fibrosis in diabetic nephropathy. Cell Death Dis, 2022, 13(6): 522.

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