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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Lin28a attenuates TGF-β-induced renal fibrosis

  • Jung, Gwon-Soo (New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Hwang, Yeo Jin (Division of Electronics & Information System, Daegu Gyeongbuk Institute of Science and Technology) ;
  • Choi, Jun-Hyuk (Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology) ;
  • Lee, Kyeong-Min (Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology)
  • Received : 2020.07.17
  • Accepted : 2020.10.05
  • Published : 2020.11.30
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Abstract

Lin28a has diverse functions including regulation of cancer, reprogramming and regeneration, but whether it promotes injury or is a protective reaction to renal injury is unknown. We studied how Lin28a acts in unilateral ureteral obstruction (UUO)-induced renal fibrosis following unilateral ureteral obstruction, in a mouse model. We further defined the role of Lin28a in transforming growth factor (TGF)-signaling pathways in renal fibrosis through in vitro study using human tubular epithelium-like HK-2 cells. In the mouse unilateral ureteral obstruction model, obstruction markedly decreased the expression of Lin28a, increased the expression of renal fibrotic markers such as type I collagen, α-SMA, vimentin and fibronectin. In TGF-β-stimulated HK-2 cells, the expression of Lin28a was reduced and the expression of renal fibrotic markers such as type I collagen, α-SMA, vimentin and fibronectin was increased. Adenovirus-mediated overexpression of Lin28a inhibited the expression of TGF-β-stimulated type I collagen, α-SMA, vimentin and fibronectin. Lin28a inhibited TGF-β-stimulated SMAD3 activity, via inhibition of SMAD3 phosphorylation, but not the MAPK pathway ERK, JNK or p38. Lin28a attenuates renal fibrosis in obstructive nephropathy, making its mechanism a possible therapeutic target for chronic kidney disease.

Keywords

References

  1. Norman JT, Orphanides C, Garcia P et al (1999) Hypoxianduced changes in extracellular matrix metabolism in renal cells. Exp Nephrol 7, 463-493 https://doi.org/10.1159/000020625
  2. Zeisberg M, Kalluri R (2004) Experimental strategies to reverse chronic renal disease. Blood Purif 22, 440-445 https://doi.org/10.1159/000080790
  3. Harris RC, Neilson EG (2006) Toward a unified theory of renal progression. Annu Rev Med 57, 365-380 https://doi.org/10.1146/annurev.med.57.121304.131342
  4. De Vecchi AF, Dratwa M, Wiedemann ME (1999) Healthcare systems and end-stage renal disease (ESRD) therapies-an international review: costs and reimbursement/funding of ESRD therapies. Nephrol Dial Transplant 14(Suppl 6), 31-41 https://doi.org/10.1093/ndt/14.suppl_6.31
  5. Remuzzi G, Benigni A, Remuzzi A (2006) Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 116, 288-296 https://doi.org/10.1172/JCI27699
  6. Border WA, Noble NA (1994) Transforming growth factor-β in tissue fibrosis. N Engl J Med 331, 1286-1292 https://doi.org/10.1056/NEJM199411103311907
  7. Nakamura T, Miller D, Ruoslahti E et al (1992) Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-β. Kidney Int 41, 1213-1221 https://doi.org/10.1038/ki.1992.183
  8. Wrana JL, Attisano L, Wieser R et al (1994) Mechanism of activation of the TGF-β receptor. Nature 370, 341-347 https://doi.org/10.1038/370341a0
  9. Massague J, Wotton D (2000) Transcriptional control by the TGF-beta Smad signaling system. EMBO J 19, 1745-1754 https://doi.org/10.1093/emboj/19.8.1745
  10. Yamamoto T, Noble NA, Cohen AH et al (1996) Expression of transforming growth factor-beta isoforms in human glomerular disease. Kidney Int 49, 461-469 https://doi.org/10.1038/ki.1996.65
  11. Klahr S (1991) New insights into the consequences and mechanisms of renal impairment in obstructive nephrophaty. Am J Kidney Dis 18, 689-699 https://doi.org/10.1016/S0272-6386(12)80611-1
  12. Klahr S, Purkerson ML (1994) The pathophysilolgy of obstructive nephrophaty: The role of vasoactive compounds in the hemodynamic and structural abnormalities of the obstructed kidney. Am J Kidney Dis 23, 219-223 https://doi.org/10.1016/s0272-6386(12)80975-9
  13. Klahr S, Morrissey J (2002) Obstructive nephrophathy and renal fibrosis. Am J Physiol 283, F861-875
  14. Piskounova E, Polytarchou C, Thornton JE et al (2011) Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell 147, 1066-1079 https://doi.org/10.1016/j.cell.2011.10.039
  15. Xu B, Huang Y (2009) Lin28 modulates cell growth and associates with a subset of cell cycle regulator mRNAs in mouse embryonic stem cells. RNA 15, 357-361 https://doi.org/10.1261/rna.1368009
  16. Balzeau J, Menezes MR, Cao S et al (2017) The LIN28/let-7 pathway in Cancer. Front Genet 8, 31
  17. Polesskaya A, Cuvellier S, Naguibneva I et al (2007) Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency. Genes Dev 21, 1125-1138 https://doi.org/10.1101/gad.415007
  18. Cimadamore F, Amador A (2013) SOX2-Lin28/let-7 pathway regulates proliferation and neurogenesis in neural precursors. Proc Natl Acad Sci U S A 110, E3017-3026 https://doi.org/10.1073/pnas.1220176110
  19. Yuan J, Nguyen CK, Liu X et al (2012) Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate feta-like lymphopoiesis. Science 335, 1195-1200 https://doi.org/10.1126/science.1216557
  20. Zhu H, Shyh-Chang N, Segre AV et al (2011) The Lin28/let-7 axis regulates glucose metabolism. Cell 147, 81-94 https://doi.org/10.1016/j.cell.2011.08.033
  21. Park JT, Kato M, Lanting L et al (2014) Repression of let-7 by transforming growth factor-β1-induced Lin28 upregulates collagen expression in glomerular mesangial cells under diabetic conditions. Am J Physiol Renal Physiol 307, F1390-1403 https://doi.org/10.1152/ajprenal.00458.2014
  22. Wang B, Jha JC, Hagiwara S et al (2014) Transforming growth factor-β1-mediated renal fibrosis is dependent on the regulation of transforming growth factor receptor 1 expression by let-7b. Kidney Int 85, 352-361 https://doi.org/10.1038/ki.2013.372
  23. Li N, Wang LJ, Xu WL et al (2019) MicroRNA-379-5p suppresses renal fibrosis by regulating the LIN28/let-7 axis in diabetic nephropathy. Int J Mol Med 44, 1619-1628
  24. Chevalier RL, Goyal S, Wolstenholme JT et al (1998) Obstructive nephropathy in the neonatal rat is attenuated by epidermal growth factor. Kidney Int 54, 38-47 https://doi.org/10.1046/j.1523-1755.1998.00966.x
  25. Chevalier RL, Forbes MS, Thornhill BA (2009) Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int 75, 1145-1152 https://doi.org/10.1038/ki.2009.86
  26. Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920 https://doi.org/10.1126/science.1151526
  27. McDaniel K, Huang L, Sato K et al (2017) The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury. J Biol Chem 292, 11336-11347. https://doi.org/10.1074/jbc.M116.773291
  28. Madison BB, Liu Q, Zhong X et al (2013) Lin28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7. Genes Dev 27, 2233-2245 https://doi.org/10.1101/gad.224659.113
  29. Molenaar JJ, Domingo-Fernández R, Ebus ME et al (2012) LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nat Genet 44, 1199-1206 https://doi.org/10.1038/ng.2436
  30. Nguyen LH, Robinton DA, Seligson MT et al (2014) Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murin models. Cancer Cell 26, 248-261 https://doi.org/10.1016/j.ccr.2014.06.018
  31. Viswanathan SR, Powers JT, Einhorn W et al (2009) Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 41, 843-848 https://doi.org/10.1038/ng.392
  32. Liang H, Liu S, Chen Y et al (2016) mi-R-26a suppresses EMT by disrupting the lin28B/let-7d axis: potential cross-talks among miRNA in IPE. J Mol Med (Berl) 94, 655-665 https://doi.org/10.1007/s00109-016-1381-8
  33. Strutz F, Zeisberg M (2006) Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol 17, 2292-2298
  34. Verrecchia F, Mauviel AJ (2002) Transforming growth factoreta signaling through the Smad pathway: Role in extracellular matrix gene expression and regulation. J Invest Dermatol 118, 211-215 https://doi.org/10.1046/j.1523-1747.2002.01641.x
  35. Yamamoto T, Nakamura T, Noble NA et al (1993) Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A 90, 1814-1818 https://doi.org/10.1073/pnas.90.5.1814
  36. Nakamura T, Ebihara I, Fukui M et al (1993) Messenger RNA expression for growth factors in glomeruli from focal glomerular sclerosis. Clin Immunol Immunopathol 66, 33-42 https://doi.org/10.1006/clin.1993.1005
  37. Yoshioka K, Takemura T, Murakami K et al (1993) Transforming growth factor-beta protein and mRNA in glomeruli in normal and diseased human kidneys. Lab Invest 68, 154-163
  38. Cheng J, Grand JP (2002) Transforming growth factor-beta signal transduction and progressive renal disease. Exp Biol Med 227, 943-956 https://doi.org/10.1177/153537020222701102
  39. Li JH, Zhu HJ, Huang XR et al (2002) Smad7 inhibits fibrotic effect of TGF-Beta on renal tubular epithelial cells by blocking Smad2 activation. J Am Soc Nephrol 13, 1464-1472 https://doi.org/10.1097/01.ASN.0000014252.37680.E4
  40. Deng B, Yang X, Liu J et al (2010) Focal adhesion kinase mediates TGF-beta1-induced renal tubular epithelial-to-mesenchymal transition in vitro. Mol Cell Biochem 340, 21-29 https://doi.org/10.1007/s11010-010-0396-7
  41. OH CJ, Kim JY, Choi YK et al (2012) Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling. PLoS One 7, e45870 https://doi.org/10.1371/journal.pone.0045870
  42. Zhou X, Zhang J, Xu C et al (2014) Curcumin ameliorates renal fibrosis by inhibiting local fibroblast proliferation and extracellular matrix deposition. J Pharmacol Sci 126, 344-350 https://doi.org/10.1254/jphs.14173FP
  43. Zhang YE (2009) Non-smad pathways in TGF-β signaling. Cell Res Res 19, 128-139 https://doi.org/10.1038/cr.2008.328
  44. Yamashita S, Maeshima A, Kojima I et al (2004) Activin A is a potent activator of renal interstitial fibroblasts. J Am Soc Nephrol 15, 91-101 https://doi.org/10.1097/01.ASN.0000103225.68136.E6