Uremic Toxin Indoxyl Sulfate and Progression of Chronic Kidney Disease

封面


如何引用文章

全文:

开放存取 开放存取
受限制的访问 ##reader.subscriptionAccessGranted##
受限制的访问 订阅或者付费存取

详细

Chronic kidney disease is a progressive disease, which is characterized by a decline in renal function due to various underlying causes. A frequent outcome shared by nearly all chronic and progressive nephropathies is renal fibrosis. Current evidence highlights multiple mechanisms involved in renal fibrosis, including natural aging processes, glomerular hyperperfusion, intratubular hypertension and hyperfiltration, alterations in the expression of mediators responsible for cellular and structural damage, etc. The progression of fibrosis is accompanied by the decline in the renal function, resulting in uremic syndrome characterized by the accumulation of various substances known as uremic toxins. They include low-molecular water-soluble compounds, protein-bound molecules, and medium-molecular compounds. Recent studies suggest that uremic toxins can contribute to the progression of fibrosis. This review summarizes data from retrospective, prospective, and experimental studies, and systematic reviews regarding the impact of uremic toxins on the progression of renal fibrosis. The data were retrieved from bibliographic databases such as MedLine, PubMed, Google Scholar, Scopus, and eLibrary. Only articles published in peer-reviewed scientific journals were included. The search strategy was based on the key terms including хроническая болезнь почек (chronic kidney disease), уремические токсины (uremic toxins), индоксил сульфат (indoxyl sulfate), фиброз почек (renal fibrosis), and эпителиально-мезенхимальный переход (epithelial-mesenchymal transition). Lists of all relevant articles and systematic reviews were manually examined. A total of 114 full-text articles were reviewed, with 60 selected for this review. The review highlights the role of indoxyl sulfate as an active contributor to renal fibrosis, rather than a consequence of chronic kidney disease.

全文:

受限制的访问

作者简介

Tatiana S. Ryabova

Military Medical Academy

编辑信件的主要联系方式.
Email: tita74@mail.ru
ORCID iD: 0000-0001-9543-9646
SPIN 代码: 5708-0212

MD, Dr.Sci. (Medicine), Associate Professor of the Nephrology and Efferent Therapy Department

俄罗斯联邦, 6, Akademika Lebedeva str., Saint Petersburg, 194044

Andrey N. Belskikh

Military Medical Academy

Email: d0c62@mail.ru
ORCID iD: 0000-0002-0421-3797
SPIN 代码: 7764-0930

Corresponding Member of RAS, MD, Dr.Sci. (Medicine), professor the Head of the Nephrology and Efferent Therapy Department

俄罗斯联邦, 6, Akademika Lebedeva str., Saint Petersburg, 194044

参考

  1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117–S314. doi: 10.1016/j.kint.2023.10.018
  2. Richet G. Early history of uremia. Kidney International. 1988;33(5): 1013–1015. doi: 10.1038/ki.1988.102
  3. Meijers B, Zadora W. Lowenstein J. A Historical Perspective on Uremia and Uremic Toxins. Toxins (Basel). 2024;16(5):227. doi: 10.3390/toxins16050227
  4. Vanholder R, Pletinck A, Schepers E, Glorieux G. Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update. Toxins (Basel). 2018;10(1):33. doi: 10.3390/toxins10010033
  5. Vanholder R, Boelaert J, Glorieux G, Eloot S. New methods and technologies for measuring uremic toxins and quantifying dialysis adequacy. Semin Dial. 2015;28:114–124. doi: 10.1111/sdi.12331
  6. Chen JH, Chiang CK. Uremic Toxins and Protein-Bound Therapeutics in AKI and CKD: Up-to-Date Evidence. Toxins. 2021;14:8–15. doi: 10.3390/toxins14010008
  7. Duranton F, Cohen G, De Smet R, et al. Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol. 2012;23:1258–1270. doi: 10.1681/ASN.201112117
  8. Rosner MH, Reis T, Husain-Syed F, et al. Classification of Uremic Toxins and Their Role in Kidney Failure. Clin J Am Soc Nephrol. 2021;16(12): 1918–1928. doi: 10.2215/CJN.02660221
  9. Leong SC, Sirich TL. Indoxyl Sulfate-Review of Toxicity and Therapeutic Strategies. Toxins (Basel). 2016;8(12):358. doi: 10.3390/toxins8120358
  10. Enomoto A, Takeda M, Tojo A, et al. Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. J Am Soc Nephrol. 2002;13:1711–1720. doi: 10.1097/01.asn.0000022017.96399.b2
  11. Poesen R, Mutsaers HA, Windey K, et al. The influence of dietary protein intake on mammalian tryptophan and phenolic metabolites. PLoS One. 2015;10:e0140820. doi: 10.1371/journal.pone.0140820
  12. Sirich TL, Funk BA, Plummer NS, et al. Prominent accumulation in hemodialysis patients of solutes normally cleared by tubular secretion. J Am Soc Nephrol. 2014;25:615–622. doi: 10.1681/ASN.201306059
  13. Hyun HS, Paik KH, Cho HY. p-Cresyl sulfate and indoxyl sulfate in pediatric patients on chronic dialysis. Korean J Pediatr. 2013;56(4):159–164. doi: 10.3345/kjp.2013.56.4.159
  14. Niwa T, Ise M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med. 1994;124(1):96–104
  15. Zschiedrich S, Bork T, Liang W, et al. Targeting mTOR Signaling Can Prevent the Progression of FSGS. J Am Soc Nephrol. 2017;28(7):2144–2157. doi: 10.1681/ASN.2016050519
  16. Gödel M, Hartleben B, Herbach N, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011;121:2197–2209. doi: 10.1172/JCI44774
  17. Nakano T, Watanabe H, Imafuku T, et al. Indoxyl Sulfate Contributes to mTORC1-Induced Renal Fibrosis via The OAT/NADPH Oxidase/ROS Pathway. Toxins (Basel). 2021;13(12):909. doi: 10.3390/toxins13120909
  18. Deguchi T, Ohtsuki S, Otagiri M, et al. Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Kidney Int. 2002;61:1760–1768. doi: 10.1046/j.1523-1755.2002.00318.x
  19. Lu CL, Liao CH, Lu KC, Ma MC. TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage. Int J Mol Sci. 2020;21(17):6212. doi: 10.3390/ijms21176212
  20. Wang WJ, Cheng MH, Sun MF, et al. Indoxyl sulfate induces renin release and apoptosis of kidney mesangial cells. J Toxicol Sci. 2014;39(4): 637–643. doi: 10.2131/jts.39.637
  21. Sheng L, Zhuang S. New Insights Into the Role and Mechanism of Partial Epithelial-Mesenchymal Transition in Kidney Fibrosis. Front Physiol. 2020;11:569322. doi: 10.3389/fphys.2020.569322
  22. Brij Mohan KS, Mathew M. Epithelial-mesenchymal transition and its role in renal fibrogenesis. Brazilian Archives of Biology and Technology. 2022;65:22210260. doi: 10.1590/1678-4324-2022210260
  23. Hajarnis S, Yheskel M, Williams D, et al. Suppression of microRNA Activity in Kidney Collecting Ducts Induces Partial Loss of Epithelial Phenotype and Renal Fibrosis. J Am Soc Nephrol. 2018;29(2):518–531. doi: 10.1681/ASN.2017030334
  24. Simon N, Hertig A. Alteration of fatty acid oxidation in tubular epithelial cells: from acute kidney injury to renal fibrogenesis. Front Med. 2015;2:52. doi: 10.3389/fmed.2015.00052
  25. Lovisa S, Zeisberg M, Kalluri R. Partial Epithelial-to-Mesenchymal transition and other new mechanisms of kidney fibrosis. Trends Endocrinol Metab. 2016;27:681. doi: 695. 10.1016/j.tem.2016.06.004
  26. Lovisa S, LeBleu V, Tampe B, et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. 2015;21:998–1009. doi: 10.1038/nm.3902
  27. Rastaldi MP, Ferrario F, Giardino L, et al. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int. 2002;62(1):137–146. doi: 10.1046/j.1523-1755.2002.00430.x
  28. Cao Y, Lin JH, Hammes HP, Zhang C. Cellular phenotypic transitions in diabetic nephropathy: An update. Front Pharmacol. 2022;13:1038073. doi: 10.3389/fphar.2022.1038073
  29. Savagner P, Brabletz T, Cheng C, et al. Twenty Years of Epithelial-Mesenchymal Transition: A State of the Field from TEMTIA X. Cells Tissues Organs. 2024;213(4):297–303. doi: 10.1159/000536096
  30. Bolati D, Shimizu H, Higashiyama Y, et al. Indoxyl sulfate induces epithelial-to-mesenchymal transition in rat kidneys and human proximal tubular cells. Am J Nephrol. 2011;34(4):318–323. doi: 10.1159/000330852
  31. Kim SH, Yu MA, Ryu ES, et al. Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease. Lab Invest. 2012;92(4):488–498. doi: 10.1038/labinvest.2011.194
  32. Chang LC, Sun HL, Tsai CH, et al. 1,25(OH)2 D3 attenuates indoxyl sulfate-induced epithelial-to-mesenchymal cell transition via inactivation of PI3K/Akt/β-catenin signaling in renal tubular epithelial cells. Nutrition. 2020;69:110554. doi: 10.1016/j.nut.2019.110554
  33. Hommos MS, Glassock RJ, Rule AD. Structural and Functional Changes in Human Kidneys with Healthy Aging. J Am Soc Nephrol. 2017;28(10): 2838–2844. doi: 10.1681/ASN.2017040421
  34. Franceschi C, Garagnani P, Parini P, et al. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576–590. doi: 10.1038/s41574-018-0059-4
  35. Yang Y, Mihajlovic M, Janssen MJ, Masereeuw R. The Uremic Toxin Indoxyl Sulfate Accelerates Senescence in Kidney Proximal Tubule Cells. Toxins (Basel). 2023;15(4):242. doi: 10.3390/toxins15040242
  36. Birch J, Gil J. Senescence and the SASP: many therapeutic avenues. Genes Dev. 2020;34(23–24):1565–1576. doi: 10.1101/gad.343129.120
  37. Yang Y, Mihajlovic M, Masereeuw R. Protein-Bound Uremic Toxins in Senescence and Kidney Fibrosis. Biomedicines. 2023;1(9):2408. doi: 10.3390/biomedicines11092408
  38. Mihajlovic M, Krebber MM, Yang Y, et al. Protein-Bound Uremic Toxins Induce Reactive Oxygen Species-Dependent and Inflammasome-Mediated IL-1beta Production in Kidney Proximal Tubule Cells. Biomedicines. 2021;9:1326. doi: 10.3390/biomedicines910132637
  39. Lee WC, Li LC, Chen JB, Chang HW. Indoxyl sulfate-induced oxidative stress, mitochondrial dysfunction, and impaired biogenesis are partly protected by vitamin C and N-acetylcysteine. Scientific World Journal. 2015;2015(1):620826. doi: 10.1155/2015/62
  40. Dou L, Jourde-Chiche N, Faure V, et al. The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells. J Thromb Haemost. 2007;5(6):1302–1308. doi: 10.1111/j.1538-7836.2007.02540
  41. Ellis RJ, Small DM, Ng KL, et al. Indoxyl Sulfate Induces Apoptosis and Hypertrophy in Human Kidney Proximal Tubular Cells. Toxicologic Pathology. 2018;46(4):449–459. doi: 10.1177/0192623318768171
  42. Mijit M, Caracciolo V, Melillo A, et al. Role of p53 in the Regulation of Cellular Senescence. Biomolecules. 2020;10:420. doi: 10.3390/biom100304
  43. Engeland K. Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ. 2022;29:946–960. doi: 10.1038/s41418-022-00988-z
  44. Ruan B, Liu W, Chen P, et al. NVP-BEZ235 inhibits thyroid cancer growth by p53-dependent/independent p21 upregulation. Int J Biol Sci. 2020;16(4):682–693. doi: 10.7150/ijbs.37592
  45. Yang Y, Mihajlovic M, Janssen MJ, Masereeuw R. The Uremic Toxin Indoxyl Sulfate Accelerates Senescence in Kidney Proximal Tubule Cells. Toxins (Basel). 2023;15(4):242. doi: 10.3390/toxins15040242
  46. Shimizu H, Yisireyili M, Nishijima F, Niwa T. Indoxyl sulfate enhances p53-TGF-β1-Smad3 pathway in proximal tubular cells. Am J Nephrol. 2013;37:97–103. doi: 10.1159/000346420
  47. Kamprom W, Tawonsawatruk T, Mas-Oodi S, et al. P-cresol and Indoxyl Sulfate Impair Osteogenic Differentiation by Triggering Mesenchymal Stem Cell Senescence. Int J Med Sci. 2021;18(3):744–755. doi: 10.7150/ijms.48492
  48. Shimi T, Butin-Israeli V, Adam SA, et al. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 2011;25:2579–2593. doi: 10.1101/gad.179515.111
  49. Ashraf S, Santerre P, Kandel R. Induced senescence of healthy nucleus pulposus cells is mediated by paracrine signaling from TNF-α-activated cells. FASEB J. 2021;35(9):21795. doi: 10.1096/fj.202002201R
  50. Rapa SF, Prisco F, Popolo A, et al. Pro-Inflammatory Effects of Indoxyl Sulfate in Mice: Impairment of Intestinal Homeostasis and Immune Response. Int J Mol Sci. 2021;22:1135. doi: 10.3390/ijms22031135
  51. Savira F, Kompa AR, Magaye R, et al. Apoptosis signal-regulating kinase 1 inhibition reverses deleterious indoxyl sulfate-mediated endothelial effects. Life Sci. 2021;272:119267. doi: 10.1016/j.lfs.2021.119267
  52. Ellis RJ, Small DM, Ng KL, et al. Indoxyl Sulfate Induces Apoptosis and Hypertrophy in Human Kidney Proximal Tubular Cells. Toxicologic Pathology. 2018;46(4):449–459. doi: 10.1177/01926233187
  53. Isaka Y. Targeting TGF-β Signaling in Kidney Fibrosis. Int J Mol Sci. 2018;19(9):2532. doi: 10.3390/ijms19092532
  54. Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009;19:128–139. doi: 10.1038/cr.2008.328
  55. Cheng TH, Ma MC, Liao MT. Indoxyl Sulfate, a Tubular Toxin, Contributes to the Development of Chronic Kidney Disease. Toxins (Basel). 2020;12(11):684. doi: 10.3390/toxins12110684
  56. Miyazaki T, Ise M, Seo H, Niwa T. Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys. Kidney Int Suppl. 1997;62:S15–22. PMID: 9350672
  57. Yisireyili M, Takeshita K, Saito S, et al. Indole-3-propionic acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory genes in proximal tubular cells. Nagoya J Med Sci. 2017;79(4):477–486. doi: 10.18999/nagjms.79.4.477
  58. Milanesi S, Garibaldi S, Saio M, et al. Indoxyl Sulfate Induces Renal Fibroblast Activation through a Targetable Heat Shock Protein 90-Dependent Pathway. Oxid Med Cell Longev. 2019;17:2050183. doi: 10.1155/2019/2050183
  59. Jia M, Lin L, Xun K, et al. Indoxyl Sulfate Aggravates Podocyte Damage through the TGF-β1/Smad/ROS Signalling Pathway. Kidney Blood Press Res. 2024;49(1):385–396. doi: 10.1159/000538858
  60. Iida S, Kohno K, Yoshimura J, et al. Carbonic-adsorbent AST-120 reduces overload of indoxyl sulfate and the plasma level of TGF-beta1 in patients with chronic renal failure. Clin Exp Nephrol. 2006;10(4):262–267. doi: 10.1007/s10157-006-0441-8

补充文件

附件文件
动作
1. JATS XML
下载

版权所有 © Eco-Vector, 2025

Creative Commons License
此作品已接受知识共享署名-非商业性使用-禁止演绎 4.0国际许可协议的许可。
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 77760 от 10.02.2020.