Blood Indoxyl Sulfate and TGF-β1 Protein and mRNA Levels in Chronic Kidney Disease: Updated Insights
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Abstract
Chronic kidney disease (CKD) is characterized by systemic inflammation and the accumulation of uremic toxins such as indoxyl sulfate (IS), which induces fibrogenic signaling via transforming growth factor-beta 1 (TGF-β1). Forty CKD patients and ten healthy controls were enrolled. IS was measured by HPLC, TGF-β1 protein by ELISA, and TGF-β1 mRNA by RT-qPCR in PBMCs. IS and TGF-β1 mRNA levels increased significantly with CKD stage, particularly in stages 3 and 4. TGF-β1 mRNA correlated with IS levels (R=0.4, P<0.01), while TGF-β1 protein levels were associated with platelet count (R=0.817, P<0.001). TGF-β1 mRNA in PBMCs may serve as an early biomarker of CKD-related fibrosis. IS is a key uremic toxin influencing fibrogenic gene expression.
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2. Lin CJ, Liu HL, Pan CF, Chuang CK, Wang TJ, Sun FJ, et al. Indoxyl sulfate in CKD. Int J Mol Sci 2022;23:428
3. 3. Niwa T. Toxins and inflammation. J Ren Nutr 2021;31:421-6.
4. Barrios C, Sarró E, Seto-Salvia N, Fernandez E, Barreiro E, Cigarrán-Guldrís S, et al. Indoxyl sulfate and renal fibrosis. Eur J Clin Invest 2022;52:e13754.
5. Edamatsu T, Fujieda A, Itoh Y, Yoshida K, Yamaguchi M, Kobayashi S, et al. AhR-mediated fibrosis. Clin Exp Nephrol 2021;25:379-86.
6. Fujii H, Kono K, Goto S, Komaba H, Fukagawa M, Yamamoto H, et al. Indoxyl sulfate and oxidative stress. Int J Mol Sci 2023;24:431.
7. Zhao J, Yang W, Zhang Y, Liu Y, Sun Y, Chen Z, et al. Fibrosis and inflammation in PBMCs. Front Physiol 2023;14:1163728.
8. Wu CJ, Huang JW, Yang CW, Chen HH, Lin SL, Chen YM, et al. PBMC profiling in CKD. Int J Mol Sci 2023;24:3311.
9. Guo J, Zhou Y, Ma X, Xu X, Qiu Y, Li D, et al. Platelet-derived TGF-β1. Redox Biol 2023;58:102543.
10. Jhawar S, Sharma P, Patel V, Thomas J, Roy-Chaudhury P, Agarwal R, et al. Platelets in renal disease. Kidney360 2023;4:627-37.
11. Zhang L, Chen J, Xie Y, Wang Z, Liu J, Li H, et al. Study design in CKD. Front Cell Dev Biol 2022;10:819284.
12. Makhlough A, Kashi AH, Shabani S, Dashti N, Hosseini F, Ghaderian SMH, et al. HPLC detection of indoxyl sulfate. J Nephropathol 2021;10:e01.
13. Schepers E, Pletinck A, Vanholder R, Glorieux G, Dhondt A, Leybaert L, et al. qPCR methodology. Toxins Basel 2021;13:804.
14. Dashti N, Esmaeili M, Farajzadegan Z. Serum levels of fibrosis markers in CKD. Acta Med Iran 2012;50:197-202.
15. Babaei M, Dashti N, Esmaeili A. Indoxyl sulfate promotes renal fibrosis. Acta Med Iran 2014;52:893-8.
16. Dashti N, Lamei N, Gerayeshnejad S. Uremic toxin levels in CKD patients. ResGate 2021.
17. Dashti N, Gerayeshnejad S. IS-TGF signaling in PBMCs of CKD patients. TUMS Rep 2023.
18. Himmelfarb J, Ikizler TA. Hemodialysis. N Engl J Med 2021;384:1795-805.
19. Shafi T, Powe NR, Meyer TW, Hwang S, Hostetter TH, Meyer DM, et al. Gut-derived toxins and renal outcomes. Kidney Int 2021;100:1151-63.
20. Wu IW, Lin CY, Chang LC, Lin PY, Lee CC, Tsai YC, et al. Biomarkers in CKD. Clin Kidney J 2022;15:877-86.
21. Rossi M, Johnson DW, Xu H, Carrero JJ, Pascoe EM, Campbell KL, et al. Uremic toxins and diet. Nutrients 2022;14:215.
22. Rysz J, Franczyk B, Ciałkowska-Rysz A, Gluba-Brzózka A, Ławiński J, Szerszenowicz E, et al. Inflammation and gene expression. Int J Mol Sci 2021;22:6732.
23. De Loor H, Meijers B, Schepers E, Poesen R, Verbeke F, Vanholder R, et al. Epigenetic regulation by indoxyl sulfate. Kidney Int Rep 2021;6:896-904.
24. Dobre M, Sedor JR, Hostetter TH, Meyer TW, Powe NR, Shafi T, et al. TGF-β signaling. Nat Rev Nephrol 2022;18:284-98.
25. Kaminski TW, Pawlak K, Mysliwiec M, Pawlak D. Transcriptomics in CKD. Int J Mol Sci 2023;24:6011.
26. Satoh M, Fujimoto S, Haruna Y, Arakawa S, Horike H, Komai N, et al. Fibrotic markers in CKD. Biochim Biophys Acta 2022;1868:166308.
27. Watanabe H, Miyamoto Y, Enoki Y, Ishima Y, Kataoka K, Tanaka R, et al. Indoxyl sulfate review. Toxins Basel 2021;13:688.
28. Madero M, García-Arroyo FE, Martínez-Maldonado M, Sánchez-Lozada LG, Rodríguez-Iturbe B, Tapia E, et al. Indoxyl sulfate–targeted therapy. Kidney Int Suppl 2022;12:52-9.
29. Yoshikawa K, Abe M, Itoh K, Okada T, Nakamura T, Tamura T, et al. Gut-kidney axis. Kidney Res Clin Pract 2021;40:609-16.
30. Lai CF, Chen TC, Huang JW, Chang FC, Lin SL, Chen YM, et al. Microbiome in CKD. Front Med Lausanne 2022;9:917200.
31. Vaziri ND. Oxidative stress and toxins. Kidney Int 2021;99:989-1001.
32. Gryp T, Vanholder R, Vaneechoutte M, Glorieux G, Verbeke F, Poesen R, et al. Gut-derived metabolites. Toxins Basel 2021;13:13.
33. Hasegawa S, Taki K, Watanabe H, Enoki Y, Miyamoto Y, Ishima Y, et al. New mechanisms of indoxyl sulfate toxicity. Toxins Basel 2022;14:398.
34. 38. Lee J, Kim H, Choi M, Park S, Kang S, Lim Y, et al. Role of fibrosis in CKD. J Transl Med 2023;21:10.
35. Kim HJ, Lee SH, Lee JY, Kim Y, Lee JE, Kim DK, et al. Gut microbiome in CKD patients. Sci Rep 2023;13:9991.
36. Patel D, Singh P, Kumar R, Sharma M, Gupta A, Khan S, et al. Early markers of fibrosis. Nephrol Dial Transplant 2024;39:e127.
2. Lin CJ, Liu HL, Pan CF, Chuang CK, Wang TJ, Sun FJ, et al. Indoxyl sulfate in CKD. Int J Mol Sci 2022;23:428
3. 3. Niwa T. Toxins and inflammation. J Ren Nutr 2021;31:421-6.
4. Barrios C, Sarró E, Seto-Salvia N, Fernandez E, Barreiro E, Cigarrán-Guldrís S, et al. Indoxyl sulfate and renal fibrosis. Eur J Clin Invest 2022;52:e13754.
5. Edamatsu T, Fujieda A, Itoh Y, Yoshida K, Yamaguchi M, Kobayashi S, et al. AhR-mediated fibrosis. Clin Exp Nephrol 2021;25:379-86.
6. Fujii H, Kono K, Goto S, Komaba H, Fukagawa M, Yamamoto H, et al. Indoxyl sulfate and oxidative stress. Int J Mol Sci 2023;24:431.
7. Zhao J, Yang W, Zhang Y, Liu Y, Sun Y, Chen Z, et al. Fibrosis and inflammation in PBMCs. Front Physiol 2023;14:1163728.
8. Wu CJ, Huang JW, Yang CW, Chen HH, Lin SL, Chen YM, et al. PBMC profiling in CKD. Int J Mol Sci 2023;24:3311.
9. Guo J, Zhou Y, Ma X, Xu X, Qiu Y, Li D, et al. Platelet-derived TGF-β1. Redox Biol 2023;58:102543.
10. Jhawar S, Sharma P, Patel V, Thomas J, Roy-Chaudhury P, Agarwal R, et al. Platelets in renal disease. Kidney360 2023;4:627-37.
11. Zhang L, Chen J, Xie Y, Wang Z, Liu J, Li H, et al. Study design in CKD. Front Cell Dev Biol 2022;10:819284.
12. Makhlough A, Kashi AH, Shabani S, Dashti N, Hosseini F, Ghaderian SMH, et al. HPLC detection of indoxyl sulfate. J Nephropathol 2021;10:e01.
13. Schepers E, Pletinck A, Vanholder R, Glorieux G, Dhondt A, Leybaert L, et al. qPCR methodology. Toxins Basel 2021;13:804.
14. Dashti N, Esmaeili M, Farajzadegan Z. Serum levels of fibrosis markers in CKD. Acta Med Iran 2012;50:197-202.
15. Babaei M, Dashti N, Esmaeili A. Indoxyl sulfate promotes renal fibrosis. Acta Med Iran 2014;52:893-8.
16. Dashti N, Lamei N, Gerayeshnejad S. Uremic toxin levels in CKD patients. ResGate 2021.
17. Dashti N, Gerayeshnejad S. IS-TGF signaling in PBMCs of CKD patients. TUMS Rep 2023.
18. Himmelfarb J, Ikizler TA. Hemodialysis. N Engl J Med 2021;384:1795-805.
19. Shafi T, Powe NR, Meyer TW, Hwang S, Hostetter TH, Meyer DM, et al. Gut-derived toxins and renal outcomes. Kidney Int 2021;100:1151-63.
20. Wu IW, Lin CY, Chang LC, Lin PY, Lee CC, Tsai YC, et al. Biomarkers in CKD. Clin Kidney J 2022;15:877-86.
21. Rossi M, Johnson DW, Xu H, Carrero JJ, Pascoe EM, Campbell KL, et al. Uremic toxins and diet. Nutrients 2022;14:215.
22. Rysz J, Franczyk B, Ciałkowska-Rysz A, Gluba-Brzózka A, Ławiński J, Szerszenowicz E, et al. Inflammation and gene expression. Int J Mol Sci 2021;22:6732.
23. De Loor H, Meijers B, Schepers E, Poesen R, Verbeke F, Vanholder R, et al. Epigenetic regulation by indoxyl sulfate. Kidney Int Rep 2021;6:896-904.
24. Dobre M, Sedor JR, Hostetter TH, Meyer TW, Powe NR, Shafi T, et al. TGF-β signaling. Nat Rev Nephrol 2022;18:284-98.
25. Kaminski TW, Pawlak K, Mysliwiec M, Pawlak D. Transcriptomics in CKD. Int J Mol Sci 2023;24:6011.
26. Satoh M, Fujimoto S, Haruna Y, Arakawa S, Horike H, Komai N, et al. Fibrotic markers in CKD. Biochim Biophys Acta 2022;1868:166308.
27. Watanabe H, Miyamoto Y, Enoki Y, Ishima Y, Kataoka K, Tanaka R, et al. Indoxyl sulfate review. Toxins Basel 2021;13:688.
28. Madero M, García-Arroyo FE, Martínez-Maldonado M, Sánchez-Lozada LG, Rodríguez-Iturbe B, Tapia E, et al. Indoxyl sulfate–targeted therapy. Kidney Int Suppl 2022;12:52-9.
29. Yoshikawa K, Abe M, Itoh K, Okada T, Nakamura T, Tamura T, et al. Gut-kidney axis. Kidney Res Clin Pract 2021;40:609-16.
30. Lai CF, Chen TC, Huang JW, Chang FC, Lin SL, Chen YM, et al. Microbiome in CKD. Front Med Lausanne 2022;9:917200.
31. Vaziri ND. Oxidative stress and toxins. Kidney Int 2021;99:989-1001.
32. Gryp T, Vanholder R, Vaneechoutte M, Glorieux G, Verbeke F, Poesen R, et al. Gut-derived metabolites. Toxins Basel 2021;13:13.
33. Hasegawa S, Taki K, Watanabe H, Enoki Y, Miyamoto Y, Ishima Y, et al. New mechanisms of indoxyl sulfate toxicity. Toxins Basel 2022;14:398.
34. 38. Lee J, Kim H, Choi M, Park S, Kang S, Lim Y, et al. Role of fibrosis in CKD. J Transl Med 2023;21:10.
35. Kim HJ, Lee SH, Lee JY, Kim Y, Lee JE, Kim DK, et al. Gut microbiome in CKD patients. Sci Rep 2023;13:9991.
36. Patel D, Singh P, Kumar R, Sharma M, Gupta A, Khan S, et al. Early markers of fibrosis. Nephrol Dial Transplant 2024;39:e127.
| Files | ||
| Issue | Vol 63 No 4 (2025) | |
| Section | Original Articles | |
| Keywords | ||
| Chronic kidney disease (CKD) Indoxyl sulfate (IS) TGF-β1(Transforming growth factor-beta1) mRNA Fibrosis PBMCs (Peripheral blood mononuclear cells) Uremic toxins Biomarkers | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Nazarinasi F, Gerayeshnejad S, Dashti N, Rahbar K. Blood Indoxyl Sulfate and TGF-β1 Protein and mRNA Levels in Chronic Kidney Disease: Updated Insights. Acta Med Iran. 2025;63(4):231-236.
