Podocyte autophagy is associated with foot process effacement and proteinuria in patients with minimal change nephrotic syndrome
Autoři:
Ayu Ogawa-Akiyama aff001; Hitoshi Sugiyama aff002; Masashi Kitagawa aff001; Keiko Tanaka aff001; Yuzuki Kano aff001; Koki Mise aff001; Nozomu Otaka aff002; Katsuyuki Tanabe aff001; Hiroshi Morinaga aff004; Masaru Kinomura aff001; Haruhito A. Uchida aff005; Jun Wada aff001
Působiště autorů:
Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
aff001; Department of Human Resource Development of Dialysis Therapy for Kidney Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
aff002; Department of Molecular Life Sciences, Tokai University School of Medicine, Kanagawa, Japan
aff003; Division of Medical Informatics, Okayama University Hospital, Okayama, Japan
aff004; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
aff005
Vyšlo v časopise:
PLoS ONE 15(1)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0228337
Souhrn
Autophagy is a cellular mechanism involved in the bulk degradation of proteins and turnover of organelle. Several studies have shown the significance of autophagy of the renal tubular epithelium in rodent models of tubulointerstitial disorder. However, the role of autophagy in the regulation of human glomerular diseases is largely unknown. The current study aimed to demonstrate morphological evidence of autophagy and its association with the ultrastructural changes of podocytes and clinical data in patients with idiopathic nephrotic syndrome, a disease in which patients exhibit podocyte injury. The study population included 95 patients, including patients with glomerular disease (minimal change nephrotic syndrome [MCNS], n = 41; idiopathic membranous nephropathy [IMN], n = 37) and 17 control subjects who underwent percutaneous renal biopsy. The number of autophagic vacuoles and the grade of foot process effacement (FPE) in podocytes were examined by electron microscopy (EM). The relationships among the expression of autophagic vacuoles, the grade of FPE, and the clinical data were determined. Autophagic vacuoles were mainly detected in podocytes by EM. The microtubule-associated protein 1 light chain 3 (LC3)-positive area was co-localized with the Wilms tumor 1 (WT1)-positive area on immunofluorescence microscopy, which suggested that autophagy occurred in the podocytes of patients with MCNS. The number of autophagic vacuoles in the podocytes was significantly correlated with the podocyte FPE score (r = -0.443, p = 0.004), the amount of proteinuria (r = 0.334, p = 0.033), and the level of serum albumin (r = -0.317, p = 0.043) in patients with MCNS. The FPE score was a significant determinant for autophagy after adjusting for the age in a multiple regression analysis in MCNS patients (p = 0.0456). However, such correlations were not observed in patients with IMN or in control subjects. In conclusion, the results indicated that the autophagy of podocytes is associated with FPE and severe proteinuria in patients with MCNS. The mechanisms underlying the activation of autophagy in association with FPE in podocytes should be further investigated in order to elucidate the pathophysiology of MCNS.
Klíčová slova:
Autophagic cell death – Biopsy – Electron microscopy – Glomeruli – Lysosomes – Proteinuria – Serum albumin – Vacuoles
Zdroje
1. Vivarelli M, Massella L, Ruggiero B, Emma F. Minimal Change Disease. Clinical journal of the American Society of Nephrology: CJASN. 2017;12(2):332–45. doi: 10.2215/CJN.05000516 27940460; PubMed Central PMCID: PMC5293332.
2. Hogan J, Radhakrishnan J. The treatment of minimal change disease in adults. Journal of the American Society of Nephrology: JASN. 2013;24(5):702–11. doi: 10.1681/ASN.2012070734 23431071.
3. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290(5497):1717–21. doi: 10.1126/science.290.5497.1717 11099404; PubMed Central PMCID: PMC2732363.
4. Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, et al. A protein conjugation system essential for autophagy. Nature. 1998;395(6700):395–8. Epub 1998/10/06. doi: 10.1038/26506 9759731.
5. Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. The Journal of cell biology. 2001;152(4):657–68. Epub 2001/03/27. PubMed Central PMCID: PMC2195787. doi: 10.1083/jcb.152.4.657 11266458
6. Sudharsan Periyasamy-Thandavan MJ, Patricia Schoenlein, and Zheng Dong. Autophagy: molecular machinery, regulation, and implications for renal pathophysiology. American journal of physiology Renal physiology. 2009;297:F244–F56. doi: 10.1152/ajprenal.00033.2009 19279132
7. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032–6. Epub 2004/11/05. doi: 10.1038/nature03029 15525940.
8. Grahammer F, Haenisch N, Steinhardt F, Sandner L, Roerden M, Arnold F, et al. mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(27):E2817–26. doi: 10.1073/pnas.1402352111 24958889; PubMed Central PMCID: PMC4103333.
9. Narita M, Young AR, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science. 2011;332(6032):966–70. doi: 10.1126/science.1205407 21512002; PubMed Central PMCID: PMC3426290.
10. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140(3):313–26. doi: 10.1016/j.cell.2010.01.028 20144757; PubMed Central PMCID: PMC2852113.
11. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. The New England journal of medicine. 2013;368(7):651–62. doi: 10.1056/NEJMra1205406 23406030.
12. Condello M, Pellegrini E, Caraglia M, Meschini S. Targeting Autophagy to Overcome Human Diseases. Int J Mol Sci. 2019;20(3). doi: 10.3390/ijms20030725 30744021; PubMed Central PMCID: PMC6387456.
13. Cuervo AM, Bergamini E, Brunk UT, Droge W, Ffrench M, Terman A. Autophagy and aging: the importance of maintaining "clean" cells. Autophagy. 2005;1(3):131–40. doi: 10.4161/auto.1.3.2017 16874025.
14. Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature. 2012;485(7397):251–5. doi: 10.1038/nature10992 22535248; PubMed Central PMCID: PMC3378041.
15. Inoue K, Kuwana H, Shimamura Y, Ogata K, Taniguchi Y, Kagawa T, et al. Cisplatin-induced macroautophagy occurs prior to apoptosis in proximal tubules in vivo. Clinical and experimental nephrology. 2010;14(2):112–22. doi: 10.1007/s10157-009-0254-7 20013139.
16. Isaka Y, Kimura T, Takabatake Y. The protective role of autophagy against aging and acute ischemic injury in kidney proximal tubular cells. Autophagy. 2011;7(9):1085–7. doi: 10.4161/auto.7.9.16465 21606682
17. Jiang M, Wei Q, Dong G, Komatsu M, Su Y, Dong Z. Autophagy in proximal tubules protects against acute kidney injury. Kidney international. 2012;82(12):1271–83. doi: 10.1038/ki.2012.261 22854643; PubMed Central PMCID: PMC3491167.
18. Kimura T, Takabatake Y, Takahashi A, Kaimori JY, Matsui I, Namba T, et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. Journal of the American Society of Nephrology: JASN. 2011;22(5):902–13. doi: 10.1681/ASN.2010070705 21493778; PubMed Central PMCID: PMC3083312.
19. Kimura T, Takahashi A, Takabatake Y, Namba T, Yamamoto T, Kaimori JY, et al. Autophagy protects kidney proximal tubule epithelial cells from mitochondrial metabolic stress. Autophagy. 2013;9(11):1876–86. doi: 10.4161/auto.25418 24128672.
20. Kume S, Uzu T, Horiike K, Chin-Kanasaki M, Isshiki K, Araki S, et al. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. The Journal of clinical investigation. 2010;120(4):1043–55. doi: 10.1172/JCI41376 20335657; PubMed Central PMCID: PMC2846062.
21. Li L, Wang ZV, Hill JA, Lin F. New autophagy reporter mice reveal dynamics of proximal tubular autophagy. Journal of the American Society of Nephrology: JASN. 2014;25(2):305–15. doi: 10.1681/ASN.2013040374 24179166; PubMed Central PMCID: PMC3904563.
22. 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(5):826–37. doi: 10.4161/auto.19419 22617445.
23. Liu WJ, Luo MN, Tan J, Chen W, Huang LZ, Yang C, et al. Autophagy activation reduces renal tubular injury induced by urinary proteins. Autophagy. 2014;10(2):243–56. doi: 10.4161/auto.27004 24345797; PubMed Central PMCID: PMC5396082.
24. Suzuki C, Isaka Y, Takabatake Y, Tanaka H, Koike M, Shibata M, et al. Participation of autophagy in renal ischemia/reperfusion injury. Biochemical and biophysical research communications. 2008;368(1):100–6. doi: 10.1016/j.bbrc.2008.01.059 18222169.
25. Takahashi A, Kimura T, Takabatake Y, Namba T, Kaimori J, Kitamura H, et al. Autophagy guards against cisplatin-induced acute kidney injury. The American journal of pathology. 2012;180(2):517–25. doi: 10.1016/j.ajpath.2011.11.001 22265049.
26. Yamahara K, Kume S, Koya D, Tanaka Y, Morita Y, Chin-Kanasaki M, et al. Obesity-Mediated Autophagy Insufficiency Exacerbates Proteinuria-induced Tubulointerstitial Lesions. Journal of the American Society of Nephrology. 2013. doi: 10.1681/asn.2012111080 24092929
27. Chen J, Chen MX, Fogo AB, Harris RC, Chen JK. mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking. Journal of the American Society of Nephrology: JASN. 2013;24(2):198–207. doi: 10.1681/ASN.2012010101 23291473; PubMed Central PMCID: PMC3559479.
28. Oshima Y, Kinouchi K, Ichihara A, Sakoda M, Kurauchi-Mito A, Bokuda K, et al. Prorenin receptor is essential for normal podocyte structure and function. Journal of the American Society of Nephrology: JASN. 2011;22(12):2203–12. doi: 10.1681/ASN.2011020202 22052048; PubMed Central PMCID: PMC3279932.
29. Riediger F, Quack I, Qadri F, Hartleben B, Park JK, Potthoff SA, et al. Prorenin receptor is essential for podocyte autophagy and survival. Journal of the American Society of Nephrology: JASN. 2011;22(12):2193–202. doi: 10.1681/ASN.2011020200 22034640; PubMed Central PMCID: PMC3279931.
30. Hartleben B, Godel M, Meyer-Schwesinger C, Liu S, Ulrich T, Kobler S, et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. The Journal of clinical investigation. 2010;120(4):1084–96. doi: 10.1172/JCI39492 20200449; PubMed Central PMCID: PMC2846040.
31. Liu WJ, Li ZH, Chen XC, Zhao XL, Zhong Z, Yang C, et al. Blockage of the lysosome-dependent autophagic pathway contributes to complement membrane attack complex-induced podocyte injury in idiopathic membranous nephropathy. Sci Rep. 2017;7(1):8643. Epub 2017/08/19. doi: 10.1038/s41598-017-07889-z 28819100; PubMed Central PMCID: PMC5561110.
32. Zeng C, Fan Y, Wu J, Shi S, Chen Z, Zhong Y, et al. Podocyte autophagic activity plays a protective role in renal injury and delays the progression of podocytopathies. J Pathol. 2014;234(2):203–13. doi: 10.1002/path.4382 24870816.
33. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53(6):982–92. doi: 10.1053/j.ajkd.2008.12.034 19339088.
34. Maruyama M, Sugiyama H, Sada K, Kobayashi M, Maeshima Y, Yamasaki Y, et al. Desmin as a marker of proteinuria in early stages of membranous nephropathy in elderly patients. Clinical nephrology. 2007;68(2):73–80. Epub 2007/08/29. doi: 10.5414/cnp68073 17722705.
35. Kobayashi M, Sugiyama H, Wang DH, Toda N, Maeshima Y, Yamasaki Y, et al. Catalase deficiency renders remnant kidneys more susceptible to oxidant tissue injury and renal fibrosis in mice. Kidney Int. 2005;68(3):1018–31. doi: 10.1111/j.1523-1755.2005.00494.x 16105032.
36. Sato S, Adachi A, Sasaki Y, Dai W. Autophagy by podocytes in renal biopsy specimens. Journal of Nippon Medical School. 2006;73(2):52–3. doi: 10.1272/jnms.73.52 16641527
37. Sato S, Kitamura H, Adachi A, Sasaki Y, Ghazizadeh M. Two types of autophagy in the podocytes in renal biopsy specimens: ultrastructural study. J Submicrosc Cytol Pathol. 2006;38(2–3):167–74. 17784646.
38. Sato S, Yanagihara T, Ghazizadeh M, Ishizaki M, Adachi A, Sasaki Y, et al. Correlation of autophagy type in podocytes with histopathological diagnosis of IgA nephropathy. Pathobiology. 2009;76(5):221–6. Epub 2009/10/10. doi: 10.1159/000228897 19816081.
39. Takiue K, Sugiyama H, Inoue T, Morinaga H, Kikumoto Y, Kitagawa M, et al. Acatalasemic mice are mildly susceptible to adriamycin nephropathy and exhibit increased albuminuria and glomerulosclerosis. BMC nephrology. 2012;13:14. doi: 10.1186/1471-2369-13-14 22443450; PubMed Central PMCID: PMC3329410.
40. Hayashi K, Sasamura H, Nakamura M, Azegami T, Oguchi H, Sakamaki Y, et al. KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria. The Journal of clinical investigation. 2014;124(6):2523–37. doi: 10.1172/JCI69557 24812666; PubMed Central PMCID: PMC4089466.
41. Inoue T, Sugiyama H, Hiki Y, Takiue K, Morinaga H, Kitagawa M, et al. Differential expression of glycogenes in tonsillar B lymphocytes in association with proteinuria and renal dysfunction in IgA nephropathy. Clinical immunology. 2010;136(3):447–55. doi: 10.1016/j.clim.2010.05.009 20538527.
42. Giannico G, Yang H, Neilson EG, Fogo AB. Dystroglycan in the diagnosis of FSGS. Clinical journal of the American Society of Nephrology: CJASN. 2009;4(11):1747–53. Epub 2009/10/08. doi: 10.2215/CJN.01510209 19808230; PubMed Central PMCID: PMC2774958.
43. Zapata-Benavides P, Arellano-Rodriguez M, Bollain YGJJ, Franco-Molina MA, Rangel-Ochoa GA, Avalos-Diaz E, et al. Cytoplasmic Localization of WT1 and Decrease of miRNA-16-1 in Nephrotic Syndrome. Biomed Res Int. 2017;2017:9531074. Epub 2017/03/17. doi: 10.1155/2017/9531074 28299339; PubMed Central PMCID: PMC5337320.
44. Sugiyama H, Yokoyama H, Sato H, Saito T, Kohda Y, Nishi S, et al. Japan Renal Biopsy Registry and Japan Kidney Disease Registry: Committee Report for 2009 and 2010. Clinical and experimental nephrology. 2013;17(2):155–73. doi: 10.1007/s10157-012-0746-8 23385776.
45. Yu Q, Qiao Y, Liu D, Liu F, Gao C, Duan J, et al. Vitamin D protects podocytes from autoantibodies induced injury in lupus nephritis by reducing aberrant autophagy. Arthritis Res Ther. 2019;21(1):19. Epub 2019/01/13. doi: 10.1186/s13075-018-1803-9 30635032; PubMed Central PMCID: PMC6330406.
46. Yamamoto-Nonaka K, Koike M, Asanuma K, Takagi M, Oliva Trejo JA, Seki T, et al. Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD. Journal of the American Society of Nephrology: JASN. 2016;27(9):2685–700. Epub 2016/01/30. doi: 10.1681/ASN.2015040366 26823550; PubMed Central PMCID: PMC5004641.
47. Bootman MD, Chehab T, Bultynck G, Parys JB, Rietdorf K. The regulation of autophagy by calcium signals: Do we have a consensus? Cell Calcium. 2018;70:32–46. doi: 10.1016/j.ceca.2017.08.005 28847414.
48. Greka A, Mundel P. Cell biology and pathology of podocytes. Annu Rev Physiol. 2012;74:299–323. doi: 10.1146/annurev-physiol-020911-153238 22054238; PubMed Central PMCID: PMC3600372.
49. D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. New England Journal of Medicine. 2011;365(25):2398–411. doi: 10.1056/NEJMra1106556 22187987
50. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, et al. Association of Trypanolytic ApoL1 Variants with Kidney Disease in African Americans. Science. 2010;329(5993):841–5. doi: 10.1126/science.1193032 20647424
51. Hayek SS, Koh KH, Grams ME, Wei C, Ko YA, Li J, et al. A tripartite complex of suPAR, APOL1 risk variants and alphavbeta3 integrin on podocytes mediates chronic kidney disease. Nature medicine. 2017;23(8):945–53. doi: 10.1038/nm.4362 28650456; PubMed Central PMCID: PMC6019326.
52. Yokoyama H, Sugiyama H, Sato H, Taguchi T, Nagata M, Matsuo S, et al. Renal disease in the elderly and the very elderly Japanese: analysis of the Japan Renal Biopsy Registry (J-RBR). Clinical and experimental nephrology. 2012;16(6):903–20. doi: 10.1007/s10157-012-0673-8 23053590.
53. Wang L, Law HKW. Immune complexes suppressed autophagy in glomerular endothelial cells. Cell Immunol. 2018;328:1–8. Epub 2018/05/21. doi: 10.1016/j.cellimm.2018.02.013 29778235.
54. Beck LH Jr. PLA2R and THSD7A: Disparate Paths to the Same Disease? Journal of the American Society of Nephrology: JASN. 2017;28(9):2579–89. Epub 2017/07/05. doi: 10.1681/ASN.2017020178 28674044; PubMed Central PMCID: PMC5576947.
55. Chévrier M, Brakch N, Céline L, Genty D, Ramdani Y, Moll S, et al. Autophagosome maturation is impaired in Fabry disease. Autophagy. 2010;6(5):589–99. doi: 10.4161/auto.6.5.11943 20431343
56. Liebau MC, Braun F, Hopker K, Weitbrecht C, Bartels V, Muller RU, et al. Dysregulated autophagy contributes to podocyte damage in Fabry's disease. PloS one. 2013;8(5):e63506. doi: 10.1371/journal.pone.0063506 23691056; PubMed Central PMCID: PMC3656911.
57. Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiological reviews. 2002;82(2):373–428. doi: 10.1152/physrev.00027.2001 11917093
58. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, et al. HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature. 2007;447(7146):859–63. doi: 10.1038/nature05853 17568747.
59. Ding Y, Kim JK, Kim SI, Na HJ, Jun SY, Lee SJ, et al. TGF-{beta}1 protects against mesangial cell apoptosis via induction of autophagy. J Biol Chem. 2010;285(48):37909–19. doi: 10.1074/jbc.M109.093724 20876581; PubMed Central PMCID: PMC2988393.
60. Fang L, Li X, Luo Y, He W, Dai C, Yang J. Autophagy inhibition induces podocyte apoptosis by activating the pro-apoptotic pathway of endoplasmic reticulum stress. Experimental cell research. 2014;322(2):290–301. doi: 10.1016/j.yexcr.2014.01.001 24424244.
61. Sugiyama H, Kashihara N, Makino H, Yamasaki Y, Ota Z. Apoptosis in glomerular sclerosis. Kidney international. 1996;49(1):103–11. doi: 10.1038/ki.1996.14 8770955
62. Sugiyama H, Kashihara N, Makino H, Yamasaki Y, Ota Z. Reactive oxygen species induce apoptosis in cultured human mesangial cells. Journal of the American Society of Nephrology. 1996;7(11):2357–63. 8959625
63. Maejima Y, Isobe M, Sadoshima J. Regulation of autophagy by Beclin 1 in the heart. J Mol Cell Cardiol. 2016;95:19–25. Epub 2015/11/08. doi: 10.1016/j.yjmcc.2015.10.032 26546165; PubMed Central PMCID: PMC4861696.
64. Iijima K, Sako M, Nozu K, Mori R, Tuchida N, Kamei K, et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet. 2014;384(9950):1273–81. doi: 10.1016/s0140-6736(14)60541-9
65. Takei T, Itabashi M, Moriyama T, Kojima C, Shiohira S, Shimizu A, et al. Effect of single-dose rituximab on steroid-dependent minimal-change nephrotic syndrome in adults. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association—European Renal Association. 2013;28(5):1225–32. doi: 10.1093/ndt/gfs515 23239834.
66. Eng KE, Panas MD, Karlsson Hedestam GB, McInerney GM. A novel quantitative flow cytometry-based assay for autophagy. Autophagy. 2010;6(5):634–41. Epub 2010/05/12. doi: 10.4161/auto.6.5.12112 20458170.
67. Kaizuka T, Morishita H, Hama Y, Tsukamoto S, Matsui T, Toyota Y, et al. An Autophagic Flux Probe that Releases an Internal Control. Mol Cell. 2016;64(4):835–49. Epub 2016/11/08. doi: 10.1016/j.molcel.2016.09.037 27818143.
68. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12(1):1–222. Epub 2016/01/23. doi: 10.1080/15548627.2015.1100356 26799652; PubMed Central PMCID: PMC4835977.
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