Autophagy in acute kidney injury and maladaptive kidney repair

Abstract

Acute kidney injury (AKI) is a major renal disease characterized by a sudden decrease in kidney function. After AKI, the kidney has the ability to repair, but if the initial injury is severe the repair may be incomplete or maladaptive and result in chronic kidney problems. Autophagy is a highly conserved pathway to deliver intracellular contents to lysosomes for degradation. Autophagy plays an important role in maintaining renal function and is involved in the pathogenesis of renal diseases. Autophagy is activated in various forms of AKI and acts as a defense mechanism against kidney cell injury and death. After AKI, autophagy is maintained at a relatively high level in kidney tubule cells during maladaptive kidney repair but the role of autophagy in maladaptive kidney repair has been controversial. Nonetheless, recent studies have demonstrated that autophagy may contribute to maladaptive kidney repair after AKI by inducing tubular degeneration and promoting a profibrotic phenotype in renal tubule cells. In this review, we analyze the role and regulation of autophagy in kidney injury and repair and discuss the therapeutic strategies by targeting autophagy.

Keywords

Autophagy / Acute kidney injury / Maladaptive repair / Fibrosis / Chronic kidney disease

References

[1] Kellum JA, Romagnani P, Ashuntantang G, Ronco C, Zarbock A, Anders H-J. Acute kidney injury. Nat Rev Dis Primers. 2021; 7: 52. https://doi.org/10.1038/s41572-021-00284-z.

[2] Linkermann A, Chen G, Dong G, Kunzendorf U, Krautwald S, Dong Z. Regulated cell death in AKI. J Am Soc Nephrol. 2014; 25: 2689-701.

[3] Maremonti F, Meyer C, Linkermann A. Mechanisms and models of kidney tubular necrosis and nephron loss. J Am Soc Nephrol. 2022; 33: 472-86.

[4] Yu SMW, Bonventre JV. Acute kidney injury and maladaptive tubular repair leading to renal fibrosis. Curr Opin Nephrol Hypertens. 2020; 29: 310-8.

[5] Ferenbach DA, Bonventre JV. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol. 2015; 11: 264-76.

[6] Djudjaj S, Boor P. Cellular and molecular mechanisms of kidney fibrosis. Mol Asp Med. 2019; 65: 16-36.

[7] Basile DP, Bonventre JV, Mehta R, Nangaku M, Unwin R, Rosner MH, et al. Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments. J Am Soc Nephrol. 2016; 27: 687-97.

[8] Humphreys BD. Mechanisms of renal fibrosis. Annu Rev Physiol. 2018; 80: 309-26.

[9] Venkatachalam MA, Weinberg JM, Kriz W, Bidani AK. Failed tubule recovery, AKI-CKD transition, and kidney disease progression. J Am Soc Nephrol. 2015; 26: 1765-76.

[10] Li L, Fu H, Liu Y. The fibrogenic niche in kidney fibrosis: components and mechanisms. Nat Rev Nephrol. 2022; 18: 545-57.

[11] Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011; 147: 728-41.

[12] Abada A, Elazar Z. Getting ready for building: signaling and autophagosome biogenesis. EMBO Rep. 2014; 15: 839-52.

[13] Lamb CA, Yoshimori T, Tooze SA. The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol. 2013; 14: 759-74.

[14] Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol. 2020; 21: 183-203.

[15] Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J. 2012; 441: 523-40.

[16] Ravanan P, Srikumar IF, Talwar P. Autophagy: the spotlight for cellular stress responses. Life Sci. 2017; 188: 53-67.

[17] Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010; 40: 280-93.

[18] Periyasamy-Thandavan S, Jiang M, Wei Q, Smith R, Yin XM, Dong Z. Autophagy is cytoprotective during cisplatin injury of renal proximal tubular cells. Kidney Int. 2008; 74: 631-40.

[19] Yang C, Kaushal V, Shah SV, Kaushal GP. Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells. Am J Physiol Renal Physiol. 2008; 294: F777-87.

[20] Jiang M, Liu K, Luo J, Dong Z. Autophagy is a renoprotective mechanism during in vitro hypoxia and in vivo ischemia-reperfusion injury. Am J Pathol. 2010; 176: 1181-92.

[21] Liu S, Hartleben B, Kretz O, Wiech T, Igarashi P, Mizushima N, et al. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy. 2012; 8: 826-37.

[22] Takahashi A, Kimura T, Takabatake Y, Namba T, Kaimori J, Kitamura H, et al. Autophagy guards against cisplatin-induced acute kidney injury. Am J Pathol. 2012; 180: 517-25.

[23] Jiang M, Wei Q, Dong G, Komatsu M, Su Y, Dong Z. Autophagy in proximal tubules protects against acute kidney injury. Kidney Int. 2012; 82: 1271-83.

[24] Shiva N, Sharma N, Kulkarni YA, Mulay SR, Gaikwad AB. Renal ischemia/reperfusion injury: An insight on in vitro and in vivo models. Life Sci. 2020; 256: 117860.

[25] Zhao H, Alam A, Soo AP, George AJT, Ma D. Ischemia-reperfusion injury reduces long term renal graft survival: mechanism and beyond. EBioMedicine. 2018; 28: 31-42.

[26] Lempiäinen J, Finckenberg P, Mervaala EE, Sankari S, Levijoki J, Mervaala EM. Caloric restriction ameliorates kidney ischaemia/reperfusion injury through PGC-1α-eNOS pathway and enhanced autophagy. Acta Physiol (Oxf). 2013; 208: 410-21.

[27] Decuypere J-P, Hutchinson S, Monbaliu D, Martinet W, Pirenne J, Jochmans I. Autophagy dynamics and modulation in a rat model of renal ischemia-reperfusion injury. Int J Mol Sci. 2020; 21: 7185. https://doi.org/10.3390/ijms21197185.

[28] Kimura T, Takabatake Y, Takahashi A, Kaimori J-y, Matsui I, Namba T, et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J Am Soc Nephrol. 2011; 22: 902-13.

[29] Zhang Y-L, Zhang J, Cui L-Y, Yang S. Autophagy activation attenuates renal ischemia-reperfusion injury in rats. Exp Biol Med (Maywood). 2015; 240: 1590-8.

[30] Xu T, Guo J, Wei M, Wang J, Yang K, Pan C, et al. Aldehyde dehydrogenase 2 protects against acute kidney injury by regulating autophagy via the Beclin-1 pathway. JCI Insight. 2021; 6: e138183. https://doi.org/10.1172/jci.insight.138183.

[31] Gong L, He J, Sun X, Li L, Zhang X, Gan H. Activation of sirtuin1 protects against ischemia/reperfusion-induced acute kidney injury. Biomed Pharmacother. 2020; 125: 110021.

[32] Wang L-T, Chen B-L, Wu C-T, Huang K-H, Chiang C-K, Hwa Liu S. Protective role of AMP-activated protein kinase-evoked autophagy on an in vitro model of ischemia/reperfusion-induced renal tubular cell injury. PLoS One. 2013; 8: e79814. https://doi.org/10.1371/journal.pone.0079814.

[33] Chandrika BB, Yang C, Ou Y, Feng X, Muhoza D, Holmes AF, et al. Endoplasmic reticulum stress-induced autophagy provides Cytoprotection from chemical hypoxia and oxidant injury and ameliorates renal ischemia-reperfusion injury. PLoS One. 2015; 10: e0140025. https://doi.org/10.1371/journal.pone.0140025.

[34] Qiu S, Chen X, Pang Y, Zhang Z. Lipocalin-2 protects against renal ischemia/reperfusion injury in mice through autophagy activation mediated by HIF1α and NF-κb crosstalk. Biomed Pharmacother. 2018; 108: 244-53.

[35] Mapuskar KA, Wen H, Holanda DG, Rastogi P, Steinbach E, Han R, et al. Persistent increase in mitochondrial superoxide mediates cisplatin-induced chronic kidney disease. Redox Biol. 2019; 20: 98-106.

[36] Pabla N, Dong Z. Dong Z : cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 2008; 73: 994-1007.

[37] Ozkok A, Edelstein CL. Pathophysiology of cisplatin-induced acute kidney injury. Biomed Res Int. 2014; 2014: 1-17.

[38] Volarevic V, Djokovic B, Jankovic MG, Harrell CR, Fellabaum C, Djonov V, et al. Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J Biomed Sci. 2019; 26: 25. https://doi.org/10.1371/journal.pone.0140025.

[39] Wang Y, Liu K, Xie X, Song B. Contrast-associated acute kidney injury: An update of risk factors, risk factor scores, and preventive measures. Clin Imaging. 2021; 69: 354-62.

[40] Kimura A, Ishida Y, Inagaki M, Nakamura Y, Sanke T, Mukaida N, et al. Interferon-γ is protective in cisplatin-induced renal injury by enhancing autophagic flux. Kidney Int. 2012; 82: 1093-104.

[41] Shen Q, Zhang X, Li Q, Zhang J, Lai H, Gan H, et al. TLR2 protects cisplatin-induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway. J Cell Biochem. 2019; 120: 4366-74.

[42] Wang Y, Liu Z, Shu S, Cai J, Tang C, Dong Z. AMPK/mTOR Signaling in autophagy regulation during cisplatin-induced acute kidney injury. Front Physiol. 2020; 11: 619730. https://doi.org/10.3389/fphys.2020.619730.

[43] Poukkanen M, Vaara ST, Pettilä V, Kaukonen KM, Korhonen AM, Hovilehto S, et al. Acute kidney injury in patients with severe sepsis in Finnish intensive care units. Acta Anaesthesiol Scand. 2013; 57: 863-72.

[44] Bellomo R, Kellum JA, Ronco C, Wald R, Martensson J, Maiden M, et al. Acute kidney injury in sepsis. Intensive Care Med. 2017; 43: 816-28.

[45] Gómez H, Kellum JA.Sepsis-induced acute kidney injury. Curr Opin Crit Care. 2016; 22: 546-53.

[46] Zhao Y, Feng X, Li B, Sha J, Wang C, Yang T, et al. Dexmedetomidine protects against lipopolysaccharide-induced acute kidney injury by enhancing autophagy through inhibition of the PI3K/AKT/mTOR pathway. Front Pharmacol. 2020; 11: 128.

[47] Mei S, Livingston M, Hao J, Li L, Mei C, Dong Z. Autophagy is activated to protect against endotoxic acute kidney injury. Sci Rep. 2016; 6: 22171. https://doi.org/10.1038/srep22171.

[48] Sun Y, Yao X, Zhang Q-J, Zhu M, Liu Z-P, Ci B, et al. Beclin-1-dependent autophagy protects the heart during sepsis. Circulation. 2018; 138: 2247-62.

[49] Sunahara S, Watanabe E, Hatano M, Swanson PE, Oami T, Fujimura L, et al. Influence of autophagy on acute kidney injury in a murine cecal ligation and puncture sepsis model. Sci Rep. 2018; 8: 1050. https://doi.org/10.1038/s41598-018-19350-w.

[50] Zhao W, Zhang L, Chen R, Lu H, Sui M, Zhu Y, et al. SIRT3 protects against acute kidney injury via AMPK/mTOR-regulated autophagy. Front Physiol. 2018; 9: 1526. https://doi.org/10.3389/fphys.2018.01526.

[51] Deng Z, Sun M, Wu J, Fang H, Cai S, An S, et al. SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation. Cell Death Dis. 2021; 12: 217. https://doi.org/10.1038/s41419-021-03508-y.

[52] Gatica D, Lahiri V, Klionsky DJ. Cargo recognition and degradation by selective autophagy. Nat Cell Biol. 2018; 20: 233-42.

[53] Tang C, Cai J, Yin XM, Weinberg JM, Venkatachalam MA, Dong Z. Mitochondrial quality control in kidney injury and repair. Nat Rev Nephrol. 2021; 17: 299-318.

[54] Su L, Zhang J, Gomez H, Kellum JA, Peng Z. Mitochondria ROS and mitophagy in acute kidney injury. Autophagy. 2022; 1-14.

[55] Wang Y, Tang C, Cai J, Chen G, Zhang D, Zhang Z, et al. PINK1/parkin-mediated mitophagy is activated in cisplatin nephrotoxicity to protect against kidney injury. Cell Death Dis. 2018; 9: 1113. https://doi.org/10.1038/s41419-018-1152-2.

[56] Tang C, Han H, Yan M, Zhu S, Liu J, Liu Z, et al. PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury. Autophagy. 2018; 14: 880-97.

[57] Wang Y, Zhu J, Liu Z, Shu S, Fu Y, Liu Y, et al. The PINK1/PARK2/optineurin pathway of mitophagy is activated for protection in septic acute kidney injury. Redox Biol. 2021; 38: 101767.

[58] Lin Q, Li S, Jiang N, Shao X, Zhang M, Jin H, et al. PINK1-parkin pathway of mitophagy protects against contrast-induced acute kidney injury via decreasing mitochondrial ROS and NLRP3 inflammasome activation. Redox Biol. 2019; 26: 101254.

[59] Gao Y, Dai X, Li Y, Li G, Lin X, Ai C, et al. Role of parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury. J Transl Med. 2020; 18: 114.

[60] Zhao C, Chen Z, Xu X, An X, Duan S, Huang Z, et al. Pink1/parkin-mediated mitophagy play a protective role in cisplatin induced renal tubular epithelial cells injury. Exp Cell Res. 2017; 350: 390-7.

[61] Tang C, Han H, Liu Z, Liu Y, Yin L, Cai J, et al. Activation of BNIP3-mediated mitophagy protects against renal ischemia-reperfusion injury. Cell Death Dis. 2019; 10: 677.

[62] Fu Z-J, Wang Z-Y, Xu L, Chen X-H, Li X-X, Liao W-T, et al. HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury. Redox Biol. 2020; 36: 101671.

[63] Livingston MJ, Wang J, Zhou J, Wu G, Ganley IG, Hill JA, et al. Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys. Autophagy. 2019; 15: 2142-62.

[64] Wang J, Zhu P, Li R, Ren J, Zhou H. Fundc1-dependent mitophagy is obligatory to ischemic preconditioning-conferred renoprotection in ischemic AKI via suppression of Drp1-mediated mitochondrial fission. Redox Biol. 2020; 30: 101415.

[65] Lin Q, Li S, Jiang N, Jin H, Shao X, Zhu X, et al. Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy. Autophagy. 2021; 17: 2975-90.

[66] Li H, Peng X, Wang Y, Cao S, Xiong L, Fan J, et al. Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis. Autophagy. 2016; 12: 1472-86.

[67] Takagaki Y, Lee SM, Dongqing Z, Kitada M, Kanasaki K, Koya D. Endothelial autophagy deficiency induces IL6-dependent endothelial mesenchymal transition and organ fibrosis. Autophagy. 2020; 16: 1905-14.

[68] Gui Z, Suo C, Wang Z, Zheng M, Fei S, Chen H, et al. Impaired ATG16L-dependent autophagy promotes renal interstitial fibrosis in chronic renal graft dysfunction through inducing EndMT by NF-κB signal pathway. Front Immunol. 2021; 12: 650424.

[69] Canaud G, Brooks CR, Kishi S, Taguchi K, Nishimura K, Magassa S, et al. Cyclin G1 and TASCC regulate kidney epithelial cell G2-M arrest and fibrotic maladaptive repair. Sci Transl Med. 2019; 11(476): eaav4754.

[70] Livingston MJ, Shu S, Fan Y, Li Z, Jiao Q, Yin X-M, et al. Tubular cells produce FGF2 via autophagy after acute kidney injury leading to fibroblast activation and renal fibrosis. Autophagy. 2023; 19(1): 256-77.

[71] Fu Y, Xiang Y, Wu W, Cai J, Tang C, Dong Z. Persistent activation of autophagy after cisplatin nephrotoxicity promotes renal fibrosis and chronic kidney disease. Front Pharmacol. 2022; 13: 918732.

[72] Li L, Kang H, Zhang Q, D’Agati VD, Al-Awqati Q, Lin F. FoxO3 activation in hypoxic tubules prevents chronic kidney disease. J Clin Invest. 2019; 129: 2374-89.

[73] Shi M, Flores B, Gillings N, Bian A, Cho HJ, Yan S, et al. αKlotho mitigates progression of AKI to CKD through activation of autophagy. J Am Soc Nephrol. 2016; 27: 2331-45.

[74] Baisantry A, Bhayana S, Rong S, Ermeling E, Wrede C, Hegermann J, et al. Autophagy induces Prosenescent changes in proximal tubular S3 segments. J Am Soc Nephrol. 2016; 27: 1609-16.

[75] Kim D-H, Park JS, Choi H-I, Kim CS, Bae EH, Ma SK, et al. The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD. Cell Death Dis. 2021; 12: 320.

[76] Pabla N, Dong G, Jiang M, Huang S, Kumar MV, Messing RO, et al. Inhibition of PKCdelta reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer. J Clin Invest. 2011; 121: 2709-22.

[77] Landau SI, Guo X, Velazquez H, Torres R, Olson E, Garcia-Milian R, et al. Regulated necrosis and failed repair in cisplatin-induced chronic kidney disease. Kidney Int. 2019; 95: 797-814.

[78] Katagiri D, Hamasaki Y, Doi K, Negishi K, Sugaya T, Nangaku M, et al. Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition. Kidney Int. 2016; 89: 374-85.

[79] Fu Y, Cai J, Li F, Liu Z, Shu S, Wang Y, et al. Chronic effects of repeated low-dose cisplatin treatment in mouse kidneys and renal tubular cells. Am J Physiol Renal Physiol. 2019; 317: F1582-92.

[80] Fu Y, Tang C, Cai J, Chen G, Zhang D, Dong Z. Rodent models of AKI-CKD transition. Am J Physiol Renal Physiol. 2018; 315: F1098-106.

[81] Sears SM, Feng JL, Orwick A, Vega AA, Krueger AM, Shah PP, et al. Pharmacological inhibitors of autophagy have opposite effects in acute and chronic cisplatin-induced kidney injury. Am J Physiol Renal Physiol. 2022; 322: F1-F12.