Research progress on programmed cell death in immunoglobulin A nephropathy_West China Medical Journal

Authors：

RAN Yingfang ¹ , CHEN Caihe ¹ ,  HUANG Wenhui ²

1. The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu 730000, P. R. China;
2. Department of Nephrology, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P. R. China;

Corresponding author：

HUANG Wenhui, Email: huangwh9966@163.com

Keywords：

Immunoglobulin A nephropathy; apoptosis; autophagy; pyroptosis; ferroptosis; cuproptosis

DOI：

10.7507/1002-0179.202407062

Video：

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Immunoglobulin A nephropathy (IgAN) is an immune-mediated chronic inflammatory disease with a complex pathogenesis and diverse clinical manifestations. Currently, there is no specific treatment plan. Programmed cell death is an active and orderly way of cell death controlled by genes in the body, which maintains the homeostasis of the body and the development of organs and tissues by participating in various molecular signaling pathways. In recent years, programmed cell death has played an important regulatory role in the occurrence and development of IgAN, involving complex signaling pathways. Under pathological conditions, it may relieve kidney damage through various pathways such as reducing oxidative stress, inhibiting inflammation, and improving energy metabolism. This article provides a review of the research progress of IgAN in apoptosis, autophagy, pyroptosis, ferroptosis,and cuproptosis in order to provide new therapeutic targets for IgAN.

Citation： RAN Yingfang, CHEN Caihe, HUANG Wenhui. Research progress on programmed cell death in immunoglobulin A nephropathy. West China Medical Journal, 2024, 39(12): 1964-1969. doi: 10.7507/1002-0179.202407062 Copy

1.	Habas E, Ali E, Farfar K, et al. IgA nephropathy pathogenesis and therapy: review & updates. Medicine (Baltimore), 2022, 101(48): e31219.
2.	Jiang P, Yao C, Guo DA. Traditional Chinese medicine for the treatment of immune-related nephropathy: a review. Acta Pharm Sin B, 2024, 14(1): 38-66.
3.	Cheng C, Yuan Y, Yuan F, et al. Acute kidney injury: exploring endoplasmic reticulum stress-mediated cell death. Front Pharmacol, 2024, 15: 1308733.
4.	Yang H, Sun J, Sun A, et al. Podocyte programmed cell death in diabetic kidney disease: molecular mechanisms and therapeutic prospects. Biomed Pharmacother, 2024, 177: 117140.
5.	Fei C, Zhen X, Shiqiang Z, et al. Frontier knowledge and future directions of programmed cell death in clear cell renal cell carcinoma. Cell Death Discov, 2024, 10(1): 113.
6.	Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol, 2019, 20(3): 175-193.
7.	Cavalcante GC, Schaan AP, Cabral GF, et al. A cell’s fate: an overview of the molecular biology and genetics of apoptosis. Int J Mol Sci, 2019, 20(17): 4133.
8.	Shi C, Cao P, Wang Y, et al. PANoptosis: A cell death characterized by pyroptosis, apoptosis, and necroptosis. J Inflamm Res, 2023, 16: 1523-1532.
9.	Knoppova B, Reily C, Maillard N, et al. The origin and activities of IgA1-containing immune complexes in IgA nephropathy. Front Immunol, 2016, 7: 117.
10.	Wan Q, Zhou J, Wu Y, et al. TNF-α-mediated podocyte injury via the apoptotic death receptor pathway in a mouse model of IgA nephropathy. Ren Fail, 2022, 44(1): 1216-1226.
11.	Levin A, Schwarz A, Hulkko J, et al. The role of dendrin in IgA nephropathy. Nephrol Dial Transplant, 2023, 38(2): 311-321.
12.	Li JJ, Li L, Li S, et al. Sinomenine hydrochloride protects IgA nephropathy through regulating cell growth and apoptosis of T and B lymphocytes. Drug Des Devel Ther, 2024, 18: 1247-1262.
13.	Takahata A, Arai S, Hiramoto E, et al. Crucial role of AIM/CD5L in the development of glomerular inflammation in IgA nephropathy. J Am Soc Nephrol, 2020, 31(9): 2013-2024.
14.	Sun Q, Liu X, Wang M, et al. Long noncoding RNA FGD5-AS1 alleviates childhood IgA nephropathy by targeting PTEN-mediated JNK/c-Jun signaling pathway via miR-196b-5p. Exp Cell Res, 2023, 424(1): 113481.
15.	Liang S, Wu YS, Li DY et al. Autophagy and renal fibrosis. Aging Dis, 2022, 13(3): 712-731.
16.	Wu C, Xiong Y, Fu F, et al. The role of autophagy in erectile dysfunction. World J Mens Health, 2024, 42: e44.
17.	Chen PA, Chang PC, Yeh WW, et al. The lncRNA TPT1-AS1 promotes the survival of neuroendocrine prostate cancer cells by facilitating autophagy. Am J Cancer Res, 2024, 14(5): 2103-2123.
18.	Zhai P, Sung EA, Shiheido-Watanabe Y, et al. Suppression of autophagy induces senescence in the heart. bioRxiv, 2024: 2024.05. 26.595978.
19.	Bhatia D, Choi ME. Autophagy in kidney disease: advances and therapeutic potential. Prog Mol Biol Transl Sci, 2020, 172: 107-133.
20.	Chang M, Shi X, Ma S, et al. Inhibition of excessive autophagy alleviates renal injury and inflammation in a rat model of immunoglobulin A nephropathy. Eur J Pharmacol, 2023, 961: 176198.
21.	Wu CY, Hua KF, Hsu WH, et al. IgA nephropathy benefits from compound K treatment by inhibiting NF-κB/NLRP3 Inflammasome and enhancing autophagy and SIRT1. J Immunol, 2020, 205(1): 202-212.
22.	Tan X, Liu Y, Liu D, et al. SUMO1 promotes mesangial cell proliferation through inhibiting autophagy in a cell model of IgA nephropathy. Front Med (Lausanne), 2022, 9: 834164.
23.	Yu M, Shen X, He W, et al. Mesangial cell-derived exosomal miR-4455 induces podocyte injury in IgA nephropathy by targeting ULK2. Oxid Med Cell Longev, 2022, 2022: 1740770.
24.	Liu D, Liu Y, Chen G, et al. Rapamycin enhances repressed autophagy and attenuates aggressive progression in a rat model of IgA nephropathy. Am J Nephrol, 2017, 45(4): 293-300.
25.	Xia M, Liu D, Tang X, et al. Dihydroartemisinin inhibits the proliferation of IgAN mesangial cells through the mTOR signaling pathway. Int Immunopharmacol, 2020, 80: 106125.
26.	Zhao L, Lan Z, Peng L, et al. Triptolide promotes autophagy to inhibit mesangial cell proliferation in IgA nephropathy via the CARD9/p38 MAPK pathway. Cell Prolif, 2022, 55(9): e13278.
27.	Zhu X, Shen X, Lin B, et al. Liuwei dihuang pills inhibit podocyte injury and alleviate IgA nephropathy by directly altering mesangial cell-derived exosome function and secretion. Front Pharmacol, 2022, 13: 889008.
28.	Wang X, Ye S, Tong L, et al. Inhibition of ROS/caspase-3/GSDME-mediated pyroptosis alleviates high glucose-induced injury in AML-12 cells. Toxicol In Vitro, 2024, 98: 105840.
29.	Jiang X, Zhu Z, Ding L, et al. ALKBH4 impedes 5-FU sensitivity through suppressing GSDME induced pyroptosis in gastric cancer. Cell Death Dis, 2024, 15(6): 435.
30.	Xiang X, Zhang J, Yue Y. Pyroptosis: a major trigger of excessive immune response in the gingiva. Oral Dis, 2024, 30(7): 4152-4160.
31.	Qin J, Yang Q, Wang Y, et al. The role of pyroptosis in heart failure and related traditional Chinese medicine treatments. Front Pharmacol, 2024, 15: 1377359.
32.	Zhou Z, Li Q. The role of pyroptosis in the pathogenesis of kidney diseases. Kidney Dis (Basel), 2023, 9(6): 443-458.
33.	Hu B, Ma K, Wang W, et al. Research progress of pyroptosis in renal diseases. Curr Med Chem, 2023, 31(40): 6656-6671.
34.	Zhang X, Chao P, Jiang H, et al. Integration of three machine learning algorithms identifies characteristic RNA binding proteins linked with diagnosis, immunity and pyroptosis of IgA nephropathy. Front Genet, 2022, 13: 975521.
35.	Liu D, Xu M, Ding LH, et al. Activation of the Nlrp3 inflammasome by mitochondrial reactive oxygen species: a novel mechanism of albumin-induced tubulointerstitial inflammation. Int J Biochem Cell Biol, 2014, 57: 7-19.
36.	Chun J, Chung H, Wang X, et al. NLRP3 localizes to the tubular epithelium in human kidney and correlates with outcome in IgA nephropathy. Sci Rep, 2016, 6: 24667.
37.	Tsai YL, Hua KF, Chen A, et al. NLRP3 inflammasome: pathogenic role and potential therapeutic target for IgA nephropathy. Sci Rep, 2017, 7: 41123.
38.	Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
39.	Huang J, Chen G, Wang J, et al. Platycodin D regulates high glucose-induced ferroptosis of HK-2 cells through glutathione peroxidase 4 (GPX4). Bioengineered, 2022, 13(3): 6627-6637.
40.	Zou Y, Palte MJ, Deik AA, et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun, 2019, 10(1): 1617.
41.	Kenny EM, Fidan E, Yang Q, et al. Ferroptosis contributes to neuronal death and functional outcome after traumatic brain injury. Crit Care Med, 2019, 47(3): 410-418.
42.	Wang H, Nishiya K, Ito H, et al. Iron deposition in renal biopsy specimens from patients with kidney diseases. Am J Kidney Dis, 2001, 38(5): 1038-1044.
43.	Wu J, Shao X, Shen J, et al. Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells. Int J Biol Sci, 2022, 18(14): 5438-5458.
44.	Tian ZY, Li Z, Chu L, et al. Iron metabolism and chronic inflammation in IgA nephropathy. Ren Fail, 2023, 45(1): 2195012.
45.	Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 2022, 375(6586): 1254-1261.
46.	Yang Y, Wu J, Wang L, et al. Copper homeostasis and cuproptosis in health and disease. MedComm (2020), 2024, 5(10): e724.
47.	Zhu Z, Song M, Ren J, et al. Copper homeostasis and cuproptosis in central nervous system diseases. Cell Death Dis, 2024, 15(11): 850.
48.	Saedi S, Tan Y, Watson SE, et al. Potential pathogenic roles of ferroptosis and cuproptosis in cadmium-induced or exacerbated cardiovascular complications in individuals with diabetes. Front Endocrinol (Lausanne), 2024, 15: 1461171.
49.	Li X, Li L, He N, et al. Pathomics signatures and cuproptosis-related genes signatures for prediction of prognosis in patients with hepatocellular carcinoma. Transl Cancer Res, 2024, 13(10): 5473-5483.
50.	Wan F, Zhong G, Ning Z, et al. Long-term exposure to copper induces autophagy and apoptosis through oxidative stress in rat kidneys. Ecotoxicol Environ Saf, 2020, 190: 110158.
51.	Ni M, Solmonson A, Pan C, et al. Functional assessment of lipoyltransferase-1 deficiency in cells, mice, and humans. Cell Rep, 2019, 27(5): 1376-1386.
52.	Lin H, Wu D, Xiao J. Identification of key cuproptosis-related genes and their targets in patients with IgAN. BMC Nephrol, 2022, 23(1): 354.
53.	Khairnar SI, Mahajan UB, Patil KR, et al. Disulfiram and its copper chelate attenuate cisplatin-induced acute nephrotoxicity in rats via reduction of oxidative stress and inflammation. Biol Trace Elem Res, 2020, 193(1): 174-184.
54.	林胜芬, 蔡小巧, 林永强, 等. 白术内酯Ⅲ纳米粒改善免疫球蛋白A肾病大鼠肠道免疫屏障功能. 中国药师, 2024, 27(6): 951-960.

1. Habas E, Ali E, Farfar K, et al. IgA nephropathy pathogenesis and therapy: review & updates. Medicine (Baltimore), 2022, 101(48): e31219.
2. Jiang P, Yao C, Guo DA. Traditional Chinese medicine for the treatment of immune-related nephropathy: a review. Acta Pharm Sin B, 2024, 14(1): 38-66.
3. Cheng C, Yuan Y, Yuan F, et al. Acute kidney injury: exploring endoplasmic reticulum stress-mediated cell death. Front Pharmacol, 2024, 15: 1308733.
4. Yang H, Sun J, Sun A, et al. Podocyte programmed cell death in diabetic kidney disease: molecular mechanisms and therapeutic prospects. Biomed Pharmacother, 2024, 177: 117140.
5. Fei C, Zhen X, Shiqiang Z, et al. Frontier knowledge and future directions of programmed cell death in clear cell renal cell carcinoma. Cell Death Discov, 2024, 10(1): 113.
6. Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol, 2019, 20(3): 175-193.
7. Cavalcante GC, Schaan AP, Cabral GF, et al. A cell’s fate: an overview of the molecular biology and genetics of apoptosis. Int J Mol Sci, 2019, 20(17): 4133.
8. Shi C, Cao P, Wang Y, et al. PANoptosis: A cell death characterized by pyroptosis, apoptosis, and necroptosis. J Inflamm Res, 2023, 16: 1523-1532.
9. Knoppova B, Reily C, Maillard N, et al. The origin and activities of IgA1-containing immune complexes in IgA nephropathy. Front Immunol, 2016, 7: 117.
10. Wan Q, Zhou J, Wu Y, et al. TNF-α-mediated podocyte injury via the apoptotic death receptor pathway in a mouse model of IgA nephropathy. Ren Fail, 2022, 44(1): 1216-1226.
11. Levin A, Schwarz A, Hulkko J, et al. The role of dendrin in IgA nephropathy. Nephrol Dial Transplant, 2023, 38(2): 311-321.
12. Li JJ, Li L, Li S, et al. Sinomenine hydrochloride protects IgA nephropathy through regulating cell growth and apoptosis of T and B lymphocytes. Drug Des Devel Ther, 2024, 18: 1247-1262.
13. Takahata A, Arai S, Hiramoto E, et al. Crucial role of AIM/CD5L in the development of glomerular inflammation in IgA nephropathy. J Am Soc Nephrol, 2020, 31(9): 2013-2024.
14. Sun Q, Liu X, Wang M, et al. Long noncoding RNA FGD5-AS1 alleviates childhood IgA nephropathy by targeting PTEN-mediated JNK/c-Jun signaling pathway via miR-196b-5p. Exp Cell Res, 2023, 424(1): 113481.
15. Liang S, Wu YS, Li DY et al. Autophagy and renal fibrosis. Aging Dis, 2022, 13(3): 712-731.
16. Wu C, Xiong Y, Fu F, et al. The role of autophagy in erectile dysfunction. World J Mens Health, 2024, 42: e44.
17. Chen PA, Chang PC, Yeh WW, et al. The lncRNA TPT1-AS1 promotes the survival of neuroendocrine prostate cancer cells by facilitating autophagy. Am J Cancer Res, 2024, 14(5): 2103-2123.
18. Zhai P, Sung EA, Shiheido-Watanabe Y, et al. Suppression of autophagy induces senescence in the heart. bioRxiv, 2024: 2024.05. 26.595978.
19. Bhatia D, Choi ME. Autophagy in kidney disease: advances and therapeutic potential. Prog Mol Biol Transl Sci, 2020, 172: 107-133.
20. Chang M, Shi X, Ma S, et al. Inhibition of excessive autophagy alleviates renal injury and inflammation in a rat model of immunoglobulin A nephropathy. Eur J Pharmacol, 2023, 961: 176198.
21. Wu CY, Hua KF, Hsu WH, et al. IgA nephropathy benefits from compound K treatment by inhibiting NF-κB/NLRP3 Inflammasome and enhancing autophagy and SIRT1. J Immunol, 2020, 205(1): 202-212.
22. Tan X, Liu Y, Liu D, et al. SUMO1 promotes mesangial cell proliferation through inhibiting autophagy in a cell model of IgA nephropathy. Front Med (Lausanne), 2022, 9: 834164.
23. Yu M, Shen X, He W, et al. Mesangial cell-derived exosomal miR-4455 induces podocyte injury in IgA nephropathy by targeting ULK2. Oxid Med Cell Longev, 2022, 2022: 1740770.
24. Liu D, Liu Y, Chen G, et al. Rapamycin enhances repressed autophagy and attenuates aggressive progression in a rat model of IgA nephropathy. Am J Nephrol, 2017, 45(4): 293-300.
25. Xia M, Liu D, Tang X, et al. Dihydroartemisinin inhibits the proliferation of IgAN mesangial cells through the mTOR signaling pathway. Int Immunopharmacol, 2020, 80: 106125.
26. Zhao L, Lan Z, Peng L, et al. Triptolide promotes autophagy to inhibit mesangial cell proliferation in IgA nephropathy via the CARD9/p38 MAPK pathway. Cell Prolif, 2022, 55(9): e13278.
27. Zhu X, Shen X, Lin B, et al. Liuwei dihuang pills inhibit podocyte injury and alleviate IgA nephropathy by directly altering mesangial cell-derived exosome function and secretion. Front Pharmacol, 2022, 13: 889008.
28. Wang X, Ye S, Tong L, et al. Inhibition of ROS/caspase-3/GSDME-mediated pyroptosis alleviates high glucose-induced injury in AML-12 cells. Toxicol In Vitro, 2024, 98: 105840.
29. Jiang X, Zhu Z, Ding L, et al. ALKBH4 impedes 5-FU sensitivity through suppressing GSDME induced pyroptosis in gastric cancer. Cell Death Dis, 2024, 15(6): 435.
30. Xiang X, Zhang J, Yue Y. Pyroptosis: a major trigger of excessive immune response in the gingiva. Oral Dis, 2024, 30(7): 4152-4160.
31. Qin J, Yang Q, Wang Y, et al. The role of pyroptosis in heart failure and related traditional Chinese medicine treatments. Front Pharmacol, 2024, 15: 1377359.
32. Zhou Z, Li Q. The role of pyroptosis in the pathogenesis of kidney diseases. Kidney Dis (Basel), 2023, 9(6): 443-458.
33. Hu B, Ma K, Wang W, et al. Research progress of pyroptosis in renal diseases. Curr Med Chem, 2023, 31(40): 6656-6671.
34. Zhang X, Chao P, Jiang H, et al. Integration of three machine learning algorithms identifies characteristic RNA binding proteins linked with diagnosis, immunity and pyroptosis of IgA nephropathy. Front Genet, 2022, 13: 975521.
35. Liu D, Xu M, Ding LH, et al. Activation of the Nlrp3 inflammasome by mitochondrial reactive oxygen species: a novel mechanism of albumin-induced tubulointerstitial inflammation. Int J Biochem Cell Biol, 2014, 57: 7-19.
36. Chun J, Chung H, Wang X, et al. NLRP3 localizes to the tubular epithelium in human kidney and correlates with outcome in IgA nephropathy. Sci Rep, 2016, 6: 24667.
37. Tsai YL, Hua KF, Chen A, et al. NLRP3 inflammasome: pathogenic role and potential therapeutic target for IgA nephropathy. Sci Rep, 2017, 7: 41123.
38. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
39. Huang J, Chen G, Wang J, et al. Platycodin D regulates high glucose-induced ferroptosis of HK-2 cells through glutathione peroxidase 4 (GPX4). Bioengineered, 2022, 13(3): 6627-6637.
40. Zou Y, Palte MJ, Deik AA, et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun, 2019, 10(1): 1617.
41. Kenny EM, Fidan E, Yang Q, et al. Ferroptosis contributes to neuronal death and functional outcome after traumatic brain injury. Crit Care Med, 2019, 47(3): 410-418.
42. Wang H, Nishiya K, Ito H, et al. Iron deposition in renal biopsy specimens from patients with kidney diseases. Am J Kidney Dis, 2001, 38(5): 1038-1044.
43. Wu J, Shao X, Shen J, et al. Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells. Int J Biol Sci, 2022, 18(14): 5438-5458.
44. Tian ZY, Li Z, Chu L, et al. Iron metabolism and chronic inflammation in IgA nephropathy. Ren Fail, 2023, 45(1): 2195012.
45. Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 2022, 375(6586): 1254-1261.
46. Yang Y, Wu J, Wang L, et al. Copper homeostasis and cuproptosis in health and disease. MedComm (2020), 2024, 5(10): e724.
47. Zhu Z, Song M, Ren J, et al. Copper homeostasis and cuproptosis in central nervous system diseases. Cell Death Dis, 2024, 15(11): 850.
48. Saedi S, Tan Y, Watson SE, et al. Potential pathogenic roles of ferroptosis and cuproptosis in cadmium-induced or exacerbated cardiovascular complications in individuals with diabetes. Front Endocrinol (Lausanne), 2024, 15: 1461171.
49. Li X, Li L, He N, et al. Pathomics signatures and cuproptosis-related genes signatures for prediction of prognosis in patients with hepatocellular carcinoma. Transl Cancer Res, 2024, 13(10): 5473-5483.
50. Wan F, Zhong G, Ning Z, et al. Long-term exposure to copper induces autophagy and apoptosis through oxidative stress in rat kidneys. Ecotoxicol Environ Saf, 2020, 190: 110158.
51. Ni M, Solmonson A, Pan C, et al. Functional assessment of lipoyltransferase-1 deficiency in cells, mice, and humans. Cell Rep, 2019, 27(5): 1376-1386.
52. Lin H, Wu D, Xiao J. Identification of key cuproptosis-related genes and their targets in patients with IgAN. BMC Nephrol, 2022, 23(1): 354.
53. Khairnar SI, Mahajan UB, Patil KR, et al. Disulfiram and its copper chelate attenuate cisplatin-induced acute nephrotoxicity in rats via reduction of oxidative stress and inflammation. Biol Trace Elem Res, 2020, 193(1): 174-184.
54. 林胜芬, 蔡小巧, 林永强, 等. 白术内酯Ⅲ纳米粒改善免疫球蛋白A肾病大鼠肠道免疫屏障功能. 中国药师, 2024, 27(6): 951-960.

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Research progress on programmed cell death in immunoglobulin A nephropathy

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