Skip to main content

Advertisement

Log in

Recent advances in understanding the role of hypoxia-inducible factor 1α in renal fibrosis

  • Nephrology - Review
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Renal fibrosis is the most common pathological manifestation of chronic kidney disease (CKD), and with numerous influencing factors, its pathogenesis is complex. Epithelial–mesenchymal transition (EMT) is known to promote the progression of renal fibrosis via alterations in the secreted proteome. Moreover, blocking or even reversing EMT can effectively reduce the degree of fibrosis. As such, targeting the key molecules responsible for promoting EMT may be an effective strategy for inhibiting renal fibrosis. Research in recent years has demonstrated that hypoxia-inducible factor 1α (HIF-1α) acts to promote renal fibrosis through regulation of EMT. However, the relationship between HIF-1α and EMT remains incompletely understood. In the present review, the underlying mechanism of the interaction between HIF-1α and EMT is explored to provide novel insight into the pathogenesis of renal fibrosis and new ideas for early targeted intervention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Liu M, Liu L, Bai M, Zhang L, Ma F, Yang X, Sun S (2018) Hypoxia-induced activation of Twist/miR-214/E-cadherin axis promotes renal tubular epithelial cell mesenchymal transition and renal fibrosis. Biochem Biophys Res Commun 495(3):2324–2330. https://doi.org/10.1016/j.bbrc.2017.12.130

    Article  CAS  PubMed  Google Scholar 

  2. Perretta-Tejedor N, Munoz-Felix JM, Duwel A, Quiros-Luis Y, Fernandez-Martin JL, Morales AI, Lopez-Hernandez FJ, Lopez-Novoa JM, Martinez-Salgado C (2018) Cardiotrophin-1 opposes renal fibrosis in mice: potential prevention of chronic kidney disease. Acta Physiol. https://doi.org/10.1111/apha.13247

    Article  Google Scholar 

  3. Lovisa S, LeBleu VS, Tampe B, Sugimoto H, Vadnagara K, Carstens JL, Wu C-C, Hagos Y, Burckhardt BC, Pentcheva-Hoang T, Nischal H, Allison JP, Zeisberg M, Kalluri R (2015) Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med 21:998. https://doi.org/10.1038/nm.3902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Prakash V, Carson BB, Feenstra JM, Dass RA, Sekyrova P, Hoshino A, Petersen J, Guo Y, Parks MM, Kurylo CM, Batchelder JE, Haller K, Hashimoto A, Rundqivst H, Condeelis JS, Allis CD, Drygin D, Nieto MA, Andang M, Percipalle P, Bergh J, Adameyko I, Farrants AO, Hartman J, Lyden D, Pietras K, Blanchard SC, Vincent CT (2019) Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease. Nat Commun 10(1):2110. https://doi.org/10.1038/s41467-019-10100-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yamaguchi J, Tanaka T, Eto N, Nangaku M (2015) Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein delta. Kidney Int 88(2):262–275. https://doi.org/10.1038/ki.2015.21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wohlrab C, Vissers MCM, Phillips E, Morrin H, Robinson BA, Dachs GU (2018) The association between ascorbate and the hypoxia-inducible factors in human renal cell carcinoma requires a functional Von Hippel-Lindau protein. Front Oncol 8:574. https://doi.org/10.3389/fonc.2018.00574

    Article  PubMed  PubMed Central  Google Scholar 

  7. Li H, Satriano J, Thomas JL, Miyamoto S, Sharma K, Pastor-Soler NM, Hallows KR, Singh P (2015) Interactions between HIF-1alpha and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease. Am J Physiol Renal Physiol 309(5):F414–428. https://doi.org/10.1152/ajprenal.00463.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chan MC, Ilott NE, Schodel J, Sims D, Tumber A, Lippl K, Mole DR, Pugh CW, Ratcliffe PJ, Ponting CP, Schofield CJ (2016) Tuning the transcriptional response to hypoxia by inhibiting hypoxia-inducible factor (HIF) prolyl and asparaginyl hydroxylases. J Biol Chem 291(39):20661–20673. https://doi.org/10.1074/jbc.M116.749291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sun Y, Zhang Y, Chi P (2018) Pirfenidone suppresses TGFbeta1induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signaling pathway. Mol Med Rep 18(4):3907–3913. https://doi.org/10.3892/mmr.2018.9423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kalluri R, Neilson EG (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Investig 112(12):1776–1784. https://doi.org/10.1172/JCI20530

    Article  CAS  PubMed  Google Scholar 

  11. Grgic I, Duffield JS, Humphreys BD (2012) The origin of interstitial myofibroblasts in chronic kidney disease. Pediatr Nephrol 27(2):183–193. https://doi.org/10.1007/s00467-011-1772-6

    Article  PubMed  Google Scholar 

  12. Sun YBY, Qu X, Caruana G, Li J (2016) The origin of renal fibroblasts/myofibroblasts and the signals that trigger fibrosis. Differentiation 92(3):102–107. https://doi.org/10.1016/j.diff.2016.05.008

    Article  CAS  PubMed  Google Scholar 

  13. Wang S, Meng XM, Ng YY, Ma FY, Zhou S, Zhang Y, Yang C, Huang XR, Xiao J, Wang YY, Ka SM, Tang YJ, Chung AC, To KF, Nikolic-Paterson DJ, Lan HY (2016) TGF-beta/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis. Oncotarget 7(8):8809–8822. https://doi.org/10.18632/oncotarget.6604

    Article  PubMed  Google Scholar 

  14. Li Q, Liu B-C, Lv L-L, Ma K-L, Zhang X-L, Phillips AO (2011) Monocytes induce proximal tubular epithelial-mesenchymal transition through NF-kappa B dependent upregulation of ICAM-1. J Cell Biochem 112(6):1585–1592. https://doi.org/10.1002/jcb.23074

    Article  CAS  PubMed  Google Scholar 

  15. Strippoli R, Loureiro J, Moreno V, Benedicto I, Pérez Lozano ML, Barreiro O, Pellinen T, Minguet S, Foronda M, Osteso MT, Calvo E, Vázquez J, López Cabrera M, del Pozo MA (2015) Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis. EMBO Mol Med 7(1):102–123. https://doi.org/10.15252/emmm.201404127

    Article  CAS  PubMed  Google Scholar 

  16. Nieto MA (2002) The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3(3):155–166. https://doi.org/10.1038/nrm757

    Article  CAS  PubMed  Google Scholar 

  17. Serocki M, Bartoszewska S, Janaszak-Jasiecka A, Ochocka RJ, Collawn JF, Bartoszewski R (2018) miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target. Angiogenesis 21(2):183–202. https://doi.org/10.1007/s10456-018-9600-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Strowitzki MJ, Cummins EP, Taylor CT (2019) Protein hydroxylation by hypoxia-inducible factor (HIF) hydroxylases: unique or ubiquitous? Cells. https://doi.org/10.3390/cells8050384

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hashimoto T, Shibasaki F (2015) Hypoxia-inducible factor as an angiogenic master switch. Front Pediatr 3:33. https://doi.org/10.3389/fped.2015.00033

    Article  PubMed  PubMed Central  Google Scholar 

  20. Singh G, Krishan P (2018) Cobalt treatment does not prevent glomerular morphological alterations in type 1 diabetic rats. Naunyn Schmiedebergs Arch Pharmacol 391(9):933–944. https://doi.org/10.1007/s00210-018-1511-7

    Article  CAS  PubMed  Google Scholar 

  21. Liu G, He L (2019) Salidroside attenuates adriamycin-induced focal segmental glomerulosclerosis by inhibiting the hypoxia-inducible factor-1α expression through phosphatidylinositol 3-kinase/protein kinase B pathway. Nephron 142(3):243–252. https://doi.org/10.1159/000497821

    Article  CAS  PubMed  Google Scholar 

  22. Hanna C, Hubchak SC, Liang X, Rozen-Zvi B, Schumacker PT, Hayashida T, Schnaper HW (2013) Hypoxia-inducible factor-2α and TGF-β signaling interact to promote normoxic glomerular fibrogenesis. Am J Physiol Renal Physiol 305(9):F1323–F1331. https://doi.org/10.1152/ajprenal.00155.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nayak BK, Shanmugasundaram K, Friedrichs WE, Cavaglierii RC, Patel M, Barnes J, Block K (2016) HIF-1 mediates renal fibrosis in OVE26 type 1 diabetic mice. Diabetes 65(5):1387–1397. https://doi.org/10.2337/db15-0519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bessho R, Takiyama Y, Takiyama T, Kitsunai H, Takeda Y, Sakagami H, Ota T (2019) Hypoxia-inducible factor-1α is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy. Sci Rep 9(1):14754–14754. https://doi.org/10.1038/s41598-019-51343-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tang L, Yi R, Yang B, Li H, Chen H, Liu Z (2012) Valsartan inhibited HIF-1α pathway and attenuated renal interstitial fibrosis in streptozotocin-diabetic rats. Diabetes Res Clin Pract 97(1):125–131. https://doi.org/10.1016/j.diabres.2012.01.037

    Article  CAS  PubMed  Google Scholar 

  26. Dhillon S (2019) Roxadustat: first global approval. Drugs 79(5):563–572. https://doi.org/10.1007/s40265-019-01077-1

    Article  CAS  PubMed  Google Scholar 

  27. Wakashima T, Tanaka T, Fukui K, Komoda Y, Shinozaki Y, Kobayashi H, Matsuo A, Nangaku M (2020) JTZ-951, an HIF prolyl hydroxylase inhibitor, suppresses renal interstitial fibroblast transformation and expression of fibrosis-related factors. Am J Physiol Renal Physiol 318(1):F14–F24. https://doi.org/10.1152/ajprenal.00323.2019

    Article  CAS  PubMed  Google Scholar 

  28. Kabei K, Tateishi Y, Shiota M, Osada-Oka M, Nishide S, Uchida J, Nakatani T, Matsunaga S, Yamaguchi T, Tomita S, Miura K (2020) Effects of orally active hypoxia inducible factor alpha prolyl hydroxylase inhibitor, FG4592 on renal fibrogenic potential in mouse unilateral ureteral obstruction model. J Pharmacol Sci 142(3):93–100. https://doi.org/10.1016/j.jphs.2019.12.002

    Article  CAS  PubMed  Google Scholar 

  29. Fu D, He C, Wei J, Zhang Z, Luo Y, Tan H, Ren C (2018) PGK1 is a potential survival biomarker and invasion promoter by regulating the HIF-1alpha-mediated epithelial-mesenchymal transition process in breast cancer. Cell Physiol Biochem 51(5):2434–2444. https://doi.org/10.1159/000495900

    Article  CAS  PubMed  Google Scholar 

  30. Wu TJ, Xu B, Zhao GH, Luo J, Luo C (2018) IL-37 suppresses migration and invasion of gallbladder cancer cells through inhibition of HIF-1alpha induced epithelial-mesenchymal transition. Eur Rev Med Pharm Sci 22(23):8179–8185. https://doi.org/10.26355/eurrev_201812_16510

    Article  Google Scholar 

  31. Huber MA, Kraut N, Beug H (2005) Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 17(5):548–558. https://doi.org/10.1016/j.ceb.2005.08.001

    Article  CAS  PubMed  Google Scholar 

  32. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Investig 117(12):3810–3820. https://doi.org/10.1172/jci30487

    Article  CAS  PubMed  Google Scholar 

  33. Kabei K, Tateishi Y, Nozaki M, Tanaka M, Shiota M, Osada-Oka M, Nishide S, Uchida J, Nakatani T, Tomita S, Miura K (2018) Role of hypoxia-inducible factor-1 in the development of renal fibrosis in mouse obstructed kidney: Special references to HIF-1 dependent gene expression of profibrogenic molecules. J Pharm Sci 136(1):31–38. https://doi.org/10.1016/j.jphs.2017.12.004

    Article  CAS  Google Scholar 

  34. Ding M, Cui S, Li C, Jothy S, Haase V, Steer BM, Marsden PA, Pippin J, Shankland S, Rastaldi MP, Cohen CD, Kretzler M, Quaggin SE (2006) Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat Med 12(9):1081–1087. https://doi.org/10.1038/nm1460

    Article  CAS  PubMed  Google Scholar 

  35. Luo R, Zhang W, Zhao C, Zhang Y, Wu H, Jin J, Zhang W, Grenz A, Eltzschig HK, Tao L, Kellems RE, Xia Y (2015) Elevated endothelial hypoxia-inducible factor-1α contributes to glomerular injury and promotes hypertensive chronic kidney disease. Hypertension 66(1):75–84. https://doi.org/10.1161/hypertensionaha.115.05578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cosgrove D, Dufek B, Meehan DT, Delimont D, Hartnett M, Samuelson G, Gratton MA, Phillips G, MacKenna DA, Bain G (2018) Lysyl oxidase like-2 contributes to renal fibrosis in Col4α3/Alport mice. Kidney Int 94(2):303–314. https://doi.org/10.1016/j.kint.2018.02.024

    Article  CAS  PubMed  Google Scholar 

  37. Schietke R, Warnecke C, Wacker I, Schödel J, Mole DR, Campean V, Amann K, Goppelt-Struebe M, Behrens J, Eckardt K-U, Wiesener MS (2010) The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1. J Biol Chem 285(9):6658–6669. https://doi.org/10.1074/jbc.M109.042424

    Article  CAS  PubMed  Google Scholar 

  38. Peinado H, Iglesias-de DC, la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, Nieto MA, Cano A, Portillo F (2005) A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. The EMBO J 24(19):3446–3458. https://doi.org/10.1038/sj.emboj.7600781

    Article  CAS  PubMed  Google Scholar 

  39. Canesin G, Cuevas EP, Santos V, López-Menéndez C, Moreno-Bueno G, Huang Y, Csiszar K, Portillo F, Peinado H, Lyden D, Cano A (2015) Lysyl oxidase-like 2 (LOXL2) and E47 EMT factor: novel partners in E-cadherin repression and early metastasis colonization. Oncogene 34(8):951–964. https://doi.org/10.1038/onc.2014.23

    Article  CAS  PubMed  Google Scholar 

  40. Chen J, Ren J, Loo WTY, Hao L, Wang M (2018) Lysyl oxidases expression and histopathological changes of the diabetic rat nephron. Mol Med Rep 17(2):2431–2441. https://doi.org/10.3892/mmr.2017.8182

    Article  CAS  PubMed  Google Scholar 

  41. Sumual S, Saad S, Tang O, Yong R, McGinn S, Chen XM, Pollock CA (2010) Differential regulation of Snail by hypoxia and hyperglycemia in human proximal tubule cells. Int J Biochem Cell Biol 42(10):1689–1697. https://doi.org/10.1016/j.biocel.2010.06.023

    Article  CAS  PubMed  Google Scholar 

  42. Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, Abbruzzese JL, Hortobagyi GN, Hung MC (2007) Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Can Res 67(19):9066–9076. https://doi.org/10.1158/0008-5472.can-07-0575

    Article  CAS  Google Scholar 

  43. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939. https://doi.org/10.1016/j.cell.2004.06.006

    Article  CAS  PubMed  Google Scholar 

  44. Lee TK, Poon RT, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL, Fan ST (2006) Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res 12(18):5369–5376. https://doi.org/10.1158/1078-0432.ccr-05-2722

    Article  CAS  PubMed  Google Scholar 

  45. Kida Y, Asahina K, Teraoka H, Gitelman I, Sato T (2007) Twist relates to tubular epithelial-mesenchymal transition and interstitial fibrogenesis in the obstructed kidney. J Histochem Cytochem 55(7):661–673. https://doi.org/10.1369/jhc.6A7157.2007

    Article  CAS  PubMed  Google Scholar 

  46. Sun S, Ning X, Zhang Y, Lu Y, Nie Y, Han S, Liu L, Du R, Xia L, He L, Fan D (2009) Hypoxia-inducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition. Kidney Int 75(12):1278–1287. https://doi.org/10.1038/ki.2009.62

    Article  CAS  PubMed  Google Scholar 

  47. Movafagh S, Raj D, Sanaei-Ardekani M, Bhatia D, Vo K, Mahmoudieh M, Rahman R, Kim EH, Harralson AF (2017) Hypoxia inducible factor 1: a urinary biomarker of kidney disease. Clin Transl Sci 10(3):201–207. https://doi.org/10.1111/cts.12445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zoccola D, Morain J, Pages G, Caminiti-Segonds N, Giuliano S, Tambutte S, Allemand D (2017) Structural and functional analysis of coral Hypoxia Inducible Factor. PLoS ONE 12(11):e0186262. https://doi.org/10.1371/journal.pone.0186262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang YJ, Na HJ, Suh MJ, Ban MJ, Byeon HK, Kim WS, Kim JW, Choi EC, Kwon HJ, Chang JW, Koh YW (2015) Hypoxia induces epithelial-mesenchymal transition in follicular thyroid cancer: involvement of regulation of twist by hypoxia inducible factor-1alpha. Yonsei Med J 56(6):1503–1514. https://doi.org/10.3349/ymj.2015.56.6.1503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yang W, Wu Z, Yang K, Han Y, Chen Y, Zhao W, Huang F, Jin Y, Jin W (2019) BMI1 promotes cardiac fibrosis in ischemia-induced heart failure via the PTEN-PI3K/Akt-mTOR signaling pathway. Am J Physiol Heart Circ Physiol 316(1):H61–H69. https://doi.org/10.1152/ajpheart.00487.2018

    Article  CAS  PubMed  Google Scholar 

  51. Kim M, Lee S, Park WH, Suh DH, Kim K, Kim YB, No JH (2018) Silencing Bmi1 expression suppresses cancer stemness and enhances chemosensitivity in endometrial cancer cells. Biomed Pharmacother 108:584–589. https://doi.org/10.1016/j.biopha.2018.09.041

    Article  CAS  PubMed  Google Scholar 

  52. Li J, Wang Y, Ge J, Li W, Yin L, Zhao Z, Liu S, Qin H, Yang J, Wang L, Ni B, Liu Y, Wang H (2018) Doublecortin-like kinase 1 (DCLK1) regulates B cell-specific moloney murine leukemia virus insertion site 1 (Bmi-1) and is associated with metastasis and prognosis in pancreatic cancer. Cell Physiol Biochem 51(1):262–277. https://doi.org/10.1159/000495228

    Article  CAS  PubMed  Google Scholar 

  53. Wu Y, Tian S, Chen Y, Ji M, Qu Y, Hou P (2019) miR-218 inhibits gastric tumorigenesis through regulating Bmi-1/Akt signaling pathway. Pathol Res Pract 215(2):243–250. https://doi.org/10.1016/j.prp.2018.10.031

    Article  CAS  PubMed  Google Scholar 

  54. Du R, Xia L, Ning X, Liu L, Sun W, Huang C, Wang H, Sun S (2014) Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal. Mol Biol Cell 25(17):2650–2659. https://doi.org/10.1091/mbc.E14-01-0044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH, Huang CH, Kao SY, Tzeng CH, Tai SK, Chang SY, Lee OK, Wu KJ (2010) Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol 12(10):982–992. https://doi.org/10.1038/ncb2099

    Article  CAS  PubMed  Google Scholar 

  56. Meng XM, Tang PM, Li J, Lan HY (2015) TGF-beta/Smad signaling in renal fibrosis. Front Physiol 6:82. https://doi.org/10.3389/fphys.2015.00082

    Article  PubMed  PubMed Central  Google Scholar 

  57. Meng XM, Lan HY (2018) Transforming growth factor-beta and renal fibrosis. Sheng li xue bao Acta Physiol Sin 70(6):612–622

    Google Scholar 

  58. Lan HY (2011) Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation. Int J Biol Sci 7(7):1056–1067

    Article  CAS  Google Scholar 

  59. Chen L, Yang T, Lu DW, Zhao H, Feng YL, Chen H, Chen DQ, Vaziri ND, Zhao YY (2018) Central role of dysregulation of TGF-beta/Smad in CKD progression and potential targets of its treatment. Biomed Pharmacother 101:670–681. https://doi.org/10.1016/j.biopha.2018.02.090

    Article  CAS  PubMed  Google Scholar 

  60. Hanna C, Hubchak SC, Liang X, Rozen-Zvi B, Schumacker PT, Hayashida T, Schnaper HW (2013) Hypoxia-inducible factor-2alpha and TGF-beta signaling interact to promote normoxic glomerular fibrogenesis. Am J Physiol Renal Physiol 305(9):F1323–1331. https://doi.org/10.1152/ajprenal.00155.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rosenberger C, Mandriota S, Jurgensen JS, Wiesener MS, Horstrup JH, Frei U, Ratcliffe PJ, Maxwell PH, Bachmann S, Eckardt KU (2002) Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. J Am Soc Nephrol JASN 13(7):1721–1732

    Article  CAS  Google Scholar 

  62. Tanaka T, Wiesener M, Bernhardt W, Eckardt KU, Warnecke C (2009) The human HIF (hypoxia-inducible factor)-3alpha gene is a HIF-1 target gene and may modulate hypoxic gene induction. Biochem J 424(1):143–151. https://doi.org/10.1042/bj20090120

    Article  CAS  PubMed  Google Scholar 

  63. Xie D, Boyle AP, Wu L, Zhai J, Kawli T, Snyder M (2013) Dynamic trans-acting factor colocalization in human cells. Cell 155(3):713–724. https://doi.org/10.1016/j.cell.2013.09.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kushida N, Nomura S, Mimura I, Fujita T, Yamamoto S, Nangaku M, Aburatani H (2016) Hypoxia-Inducible factor-1alpha activates the transforming growth factor-beta/SMAD3 pathway in kidney tubular epithelial cells. Am J Nephrol 44(4):276–285. https://doi.org/10.1159/000449323

    Article  CAS  PubMed  Google Scholar 

  65. Huber TB, Edelstein CL, Hartleben B, Inoki K, Jiang M, Koya D, Kume S, Lieberthal W, Pallet N, Quiroga A, Ravichandran K, Susztak K, Yoshida S, Dong Z (2012) Emerging role of autophagy in kidney function, diseases and aging. Autophagy 8(7):1009–1031. https://doi.org/10.4161/auto.19821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hu H, Hu S, Xu S, Gao Y, Zeng F, Shui H (2018) miR-29b regulates Ang II-induced EMT of rat renal tubular epithelial cells via targeting PI3K/AKT signaling pathway. Int J Mol Med 42(1):453–460. https://doi.org/10.3892/ijmm.2018.3579

    Article  CAS  PubMed  Google Scholar 

  67. Xue M, Cheng Y, Han F, Chang Y, Yang Y, Li X, Chen L, Lu Y, Sun B, Chen L (2018) Triptolide attenuates renal tubular epithelial-mesenchymal transition via the MiR-188-5p-mediated PI3K/AKT pathway in diabetic kidney disease. Int J Biol Sci 14(11):1545–1557. https://doi.org/10.7150/ijbs.24032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liu M, Ning X, Li R, Yang Z, Yang X, Sun S, Qian Q (2017) Signalling pathways involved in hypoxia-induced renal fibrosis. J Cell Mol Med 21(7):1248–1259. https://doi.org/10.1111/jcmm.13060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang X, Guan T, Yang B, Chi Z, Wan Q, Gu HF (2019) Protective effect of berberine on high glucose and hypoxia-induced apoptosis via the modulation of HIF-1alpha in renal tubular epithelial cells. Am J Transl Res 11(2):669–682

    PubMed  PubMed Central  Google Scholar 

  70. Zhang X, Liang D, Fan J, Lian X, Zhao Y, Wang X, Chi ZH, Zhang P (2016) Zinc attenuates tubulointerstitial fibrosis in diabetic nephropathy via inhibition of HIF through PI-3K signaling. Biol Trace Elem Res 173(2):372–383. https://doi.org/10.1007/s12011-016-0661-z

    Article  CAS  PubMed  Google Scholar 

  71. Song LB, Li J, Liao WT, Feng Y, Yu CP, Hu LJ, Kong QL, Xu LH, Zhang X, Liu WL, Li MZ, Zhang L, Kang TB, Fu LW, Huang WL, Xia YF, Tsao SW, Li M, Band V, Band H, Shi QH, Zeng YX, Zeng MS (2009) The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Investig 119(12):3626–3636. https://doi.org/10.1172/jci39374

    Article  CAS  PubMed  Google Scholar 

  72. Blanco-Aparicio C, Renner O, Leal JF, Carnero A (2007) PTEN, more than the AKT pathway. Carcinogenesis 28(7):1379–1386. https://doi.org/10.1093/carcin/bgm052

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research received no external funding.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yujun Du.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wei, X., Zhu, X., Jiang, L. et al. Recent advances in understanding the role of hypoxia-inducible factor 1α in renal fibrosis. Int Urol Nephrol 52, 1287–1295 (2020). https://doi.org/10.1007/s11255-020-02474-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-020-02474-2

Keywords

Navigation