Skip to main content
SpringerLink
Log in
Book cover

Fibrosis in Disease pp 419–449Cite as

Tipping the Balance from Angiogenesis to Fibrosis in Chronic Kidney Disease

  • Chapter
  • First Online:

  • 905 Accesses

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

Abstract

The kidneys are innately under a low oxygen tension condition that originates from their unique and complicated vasculature. In chronic kidney disease (CKD), renal hypoxia occurs, and peritubular capillary rarefaction contributes to renal hypoxia. Interventions to angiogenic factors such as vascular endothelial growth factor (VEGF) and angiopoietin affect the development or maintenance of normal kidney structure. VEGF is mainly excreted from tubular cells and affects both endothelial cells and podocytes. Both low and high VEGF levels are injurious to the kidney; insufficient VEGF results in endothelial dysfunction, while excessive VEGF damages the glomeruli in a manner resembling diabetic kidney disease (DKD). The importance of angiopoietins is shown in atherosclerosis in CKD in both clinical patients and experimental animal models, while evidence of the effect of angiopoietins on CKD progression remains limited. Another important player is hypoxia. Clinical epidemiology findings have shown that renal hypoxia is involved in the pathogenesis and progression of CKD. Hypoxia-inducible factors (HIFs) govern the cellular response to hypoxia and have both angiogenetic and fibrogenic effects. The administration of VEGF, a HIF stabilizer, or progenitor cells leads to peritubular capillary maintenance, followed by renal fibrosis alleviation. Indoxyl sulfate is a representative uremic toxin and pathological factor that causes the imbalance between angiogenesis and fibrosis and subsequent insufficient HIF activation. The treatment of uremic toxins has the potential to adjust this angiogenesis–fibrosis imbalance.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Safran M, et al. Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production. Proc Natl Acad Sci U S A. 2006;103:105–10. https://doi.org/10.1073/pnas.0509459103.

    Article  CAS  PubMed  Google Scholar 

  2. van Bommel J, Siegemund M, Henny C,P, Ince C. Heart, kidney, and intestine have different tolerances for anemia. Transl Res. 2008;151:110–7. https://doi.org/10.1016/j.trsl.2007.11.001.

    Article  PubMed  Google Scholar 

  3. Mimura I, Nangaku M. The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. Nat Rev Nephrol. 2010;6:667–78. https://doi.org/10.1038/nrneph.2010.124.

    Article  CAS  PubMed  Google Scholar 

  4. Schurek HJ, Jost U, Baumgartl H, Bertram H, Heckmann U. Evidence for a preglomerular oxygen diffusion shunt in rat renal cortex. Am J Phys. 1990;259:F910–5.

    CAS  Google Scholar 

  5. Ngo JP, et al. Vascular geometry and oxygen diffusion in the vicinity of artery-vein pairs in the kidney. Am J Physiol Renal Physiol. 2014;307:F1111–22. https://doi.org/10.1152/ajprenal.00382.2014.

    Article  CAS  PubMed  Google Scholar 

  6. Olgac U, Kurtcuoglu V. Renal oxygenation: preglomerular vasculature is an unlikely contributor to renal oxygen shunting. Am J Physiol Renal Physiol. 2015;308:F671–88. https://doi.org/10.1152/ajprenal.00551.2014.

    Article  CAS  PubMed  Google Scholar 

  7. O’Neill J, et al. Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. Am J Physiol Renal Physiol. 2015;309:F227–34. https://doi.org/10.1152/ajprenal.00689.2014.

    Article  CAS  PubMed  Google Scholar 

  8. Calzavacca P, et al. Long-term measurement of renal cortical and medullary tissue oxygenation and perfusion in unanesthetized sheep. Am J Physiol Regul Integr Comp Physiol. 2015;308:R832–9. https://doi.org/10.1152/ajpregu.00515.2014.

    Article  CAS  PubMed  Google Scholar 

  9. Harris DC, Chan L, Schrier RW. Remnant kidney hypermetabolism and progression of chronic renal failure. Am J Phys. 1988;254:F267–76.

    Article  CAS  Google Scholar 

  10. Deng A, et al. Renal protection in chronic kidney disease: hypoxia-inducible factor activation vs. angiotensin II blockade. Am J Physiol Renal Physiol. 2010;299:F1365–73. https://doi.org/10.1152/ajprenal.00153.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Adler S, Huang H. Impaired regulation of renal oxygen consumption in spontaneously hypertensive rats. J Am Soc Nephrol. 2002;13:1788–94.

    Article  CAS  Google Scholar 

  12. Korner A, Eklof AC, Celsi G, Aperia A. Increased renal metabolism in diabetes. Mechanism and functional implications. Diabetes. 1994;43:629–33.

    Article  CAS  Google Scholar 

  13. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 2006;17:17–25. https://doi.org/10.1681/asn.2005070757.

    Article  CAS  PubMed  Google Scholar 

  14. Lindenmeyer MT, et al. Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy. J Am Soc Nephrol. 2007;18:1765–76. https://doi.org/10.1681/asn.2006121304.

    Article  CAS  PubMed  Google Scholar 

  15. Kaukinen A, Lautenschlager I, Helin H, Karikoski R, Jalanko H. Peritubular capillaries are rarefied in congenital nephrotic syndrome of the Finnish type. Kidney Int. 2009;75:1099–108. https://doi.org/10.1038/ki.2009.41.

    Article  PubMed  Google Scholar 

  16. Yuan HT, Li XZ, Pitera JE, Long DA, Woolf AS. Peritubular capillary loss after mouse acute nephrotoxicity correlates with down-regulation of vascular endothelial growth factor-A and hypoxia-inducible factor-1 alpha. Am J Pathol. 2003;163:2289–301.

    Article  CAS  Google Scholar 

  17. Ohashi R, et al. Peritubular capillary regression during the progression of experimental obstructive nephropathy. J Am Soc Nephrol. 2002;13:1795–805.

    Article  Google Scholar 

  18. Kang DH, et al. Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1. J Am Soc Nephrol. 2001;12:1434–47.

    CAS  PubMed  Google Scholar 

  19. Futatsugi K, et al. Obesity-induced kidney injury is attenuated by amelioration of aberrant PHD2 activation in proximal tubules. Sci Rep. 2016;6:36533. https://doi.org/10.1038/srep36533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tanaka S, Tanaka T, Nangaku M. Hypoxia as a key player in the AKI-to-CKD transition. Am J Physiol Renal Physiol. 2014;307:F1187–95. https://doi.org/10.1152/ajprenal.00425.2014.

    Article  CAS  PubMed  Google Scholar 

  21. Kramann R, Tanaka M, Humphreys BD. Fluorescence microangiography for quantitative assessment of peritubular capillary changes after AKI in mice. J Am Soc Nephrol. 2014;25:1924–31. https://doi.org/10.1681/asn.2013101121.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999;13:9–22.

    Article  CAS  Google Scholar 

  23. Tanaka T, Nangaku M. Angiogenesis and hypoxia in the kidney. Nat Rev Nephrol. 2013;9:211–22. https://doi.org/10.1038/nrneph.2013.35.

    Article  CAS  PubMed  Google Scholar 

  24. Simon M, et al. Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney. Am J Phys. 1995;268:F240–50.

    CAS  Google Scholar 

  25. Brown LF, et al. Vascular permeability factor mRNA and protein expression in human kidney. Kidney Int. 1992;42:1457–61.

    Article  CAS  Google Scholar 

  26. Simon M, et al. Receptors of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in fetal and adult human kidney: localization and [125I]VEGF binding sites. J Am Soc Nephrol. 1998;9:1032–44.

    CAS  PubMed  Google Scholar 

  27. Summers AM, et al. VEGF -460 genotype plays an important role in progression to chronic kidney disease stage 5. Nephrol Dial Transplant. 2005;20:2427–32. https://doi.org/10.1093/ndt/gfi029.

    Article  CAS  PubMed  Google Scholar 

  28. Donderski R, et al. Analysis of relative expression level of VEGF ( vascular endothelial growth factor ), HIF-1alpha ( hypoxia inducible factor 1alpha ) and CTGF ( connective tissue growth factor ) genes in chronic glomerulonephritis (CGN) patients. Kidney Blood Press Res. 2013;38:83–91. https://doi.org/10.1159/000355754.

    Article  CAS  PubMed  Google Scholar 

  29. Chen YT, et al. Value and level of circulating endothelial progenitor cells, angiogenesis factors and mononuclear cell apoptosis in patients with chronic kidney disease. Clin Exp Nephrol. 2013;17:83–91. https://doi.org/10.1007/s10157-012-0664-9.

    Article  CAS  PubMed  Google Scholar 

  30. Hohenstein B, et al. Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man. Kidney Int. 2006;69:1654–61. https://doi.org/10.1038/sj.ki.5000294.

    Article  CAS  PubMed  Google Scholar 

  31. Foster RR, et al. Functional evidence that vascular endothelial growth factor may act as an autocrine factor on human podocytes. Am J Physiol Renal Physiol. 2003;284:F1263–73. https://doi.org/10.1152/ajprenal.00276.2002.

    Article  CAS  PubMed  Google Scholar 

  32. Ku CH, et al. Inducible overexpression of sFlt-1 in podocytes ameliorates glomerulopathy in diabetic mice. Diabetes. 2008;57:2824–33. https://doi.org/10.2337/db08-0647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kosugi T, et al. Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice. Am J Physiol Renal Physiol. 2010;298:F609–16. https://doi.org/10.1152/ajprenal.00377.2009.

    Article  CAS  PubMed  Google Scholar 

  34. Oltean S, et al. Vascular endothelial growth factor-A165b is protective and restores endothelial glycocalyx in diabetic nephropathy. J Am Soc Nephrol. 2015;26:1889–904. https://doi.org/10.1681/asn.2014040350.

    Article  CAS  PubMed  Google Scholar 

  35. Ferrara N, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature. 1996;380:439–42. https://doi.org/10.1038/380439a0.

    Article  CAS  PubMed  Google Scholar 

  36. Carmeliet P, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380:435–9. https://doi.org/10.1038/380435a0.

    Article  CAS  PubMed  Google Scholar 

  37. Eremina V, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358:1129–36. https://doi.org/10.1056/NEJMoa0707330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Izzedine H, et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center. Medicine (Baltimore). 2014;93:333–9. https://doi.org/10.1097/md.0000000000000207.

    Article  CAS  Google Scholar 

  39. Vigneau C, et al. All anti-vascular endothelial growth factor drugs can induce ‘pre-eclampsia-like syndrome’: a RARe study. Nephrol Dial Transplant. 2014;29:325–32. https://doi.org/10.1093/ndt/gft465.

    Article  CAS  PubMed  Google Scholar 

  40. Izzedine H, et al. Expression patterns of RelA and c-mip are associated with different glomerular diseases following anti-VEGF therapy. Kidney Int. 2014;85:457–70. https://doi.org/10.1038/ki.2013.344.

    Article  CAS  PubMed  Google Scholar 

  41. Eremina V, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest. 2003;111:707–16. https://doi.org/10.1172/jci17423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Veron D, et al. Acute podocyte vascular endothelial growth factor (VEGF-A) knockdown disrupts alphaVbeta3 integrin signaling in the glomerulus. PLoS One. 2012;7:e40589. https://doi.org/10.1371/journal.pone.0040589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu E, et al. Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions. J Am Soc Nephrol. 2007;18:2094–104. https://doi.org/10.1681/asn.2006010075.

    Article  CAS  PubMed  Google Scholar 

  44. Sato W, et al. Selective stimulation of VEGFR2 accelerates progressive renal disease. Am J Pathol. 2011;179:155–66. https://doi.org/10.1016/j.ajpath.2011.03.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Veron D, et al. Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int. 2010;77:989–99. https://doi.org/10.1038/ki.2010.64.

    Article  CAS  PubMed  Google Scholar 

  46. Veron D, et al. Podocyte-specific VEGF-a gain of function induces nodular glomerulosclerosis in eNOS null mice. J Am Soc Nephrol. 2014;25:1814–24. https://doi.org/10.1681/asn.2013070752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ma J, et al. Induction of podocyte-derived VEGF ameliorates podocyte injury and subsequent abnormal glomerular development caused by puromycin aminonucleoside. Pediatr Res. 2011;70:83–9. https://doi.org/10.1203/PDR.0b013e31821bdf1c.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hakroush S, et al. Effects of increased renal tubular vascular endothelial growth factor (VEGF) on fibrosis, cyst formation, and glomerular disease. Am J Pathol. 2009;175:1883–95. https://doi.org/10.2353/ajpath.2009.080792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Di Marco GS, et al. The soluble VEGF receptor sFlt1 contributes to endothelial dysfunction in CKD. J Am Soc Nephrol. 2009;20:2235–45. https://doi.org/10.1681/asn.2009010061.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Hara A, et al. Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis. Kidney Int. 2006;69:1986–95. https://doi.org/10.1038/sj.ki.5000439.

    Article  CAS  PubMed  Google Scholar 

  51. Jin J, et al. Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell. 2012;151:384–99. https://doi.org/10.1016/j.cell.2012.08.037.

    Article  CAS  PubMed  Google Scholar 

  52. Maynard SE, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649–58. https://doi.org/10.1172/jci17189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Levine RJ, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350:672–83. https://doi.org/10.1056/NEJMoa031884.

    Article  CAS  PubMed  Google Scholar 

  54. Onoue K, et al. Reduction of circulating soluble fms-like tyrosine kinase-1 plays a significant role in renal dysfunction-associated aggravation of atherosclerosis. Circulation. 2009;120:2470–7. https://doi.org/10.1161/circulationaha.109.867929.

    Article  CAS  PubMed  Google Scholar 

  55. Matsui M, et al. Suppressed soluble Fms-like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease. Kidney Int. 2014;85:393–403. https://doi.org/10.1038/ki.2013.339.

    Article  CAS  PubMed  Google Scholar 

  56. Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10:165–77. https://doi.org/10.1038/nrm2639.

    Article  CAS  PubMed  Google Scholar 

  57. Oh H, et al. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem. 1999;274:15732–9.

    Article  CAS  Google Scholar 

  58. Saharinen P, et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol. 2008;10:527–37. https://doi.org/10.1038/ncb1715.

    Article  CAS  PubMed  Google Scholar 

  59. David S, et al. Angiopoietin 2 and cardiovascular disease in dialysis and kidney transplantation. Am J Kidney Dis. 2009;53:770–8. https://doi.org/10.1053/j.ajkd.2008.11.030.

    Article  CAS  PubMed  Google Scholar 

  60. David S, et al. Circulating angiopoietin-2 levels increase with progress of chronic kidney disease. Nephrol Dial Transplant. 2010;25:2571–6. https://doi.org/10.1093/ndt/gfq060.

    Article  CAS  PubMed  Google Scholar 

  61. David S, et al. Angiopoietin-2 levels predict mortality in CKD patients. Nephrol Dial Transplant. 2012;27:1867–72. https://doi.org/10.1093/ndt/gfr551.

    Article  CAS  PubMed  Google Scholar 

  62. Chang FC, et al. Angiopoietin-2 is associated with albuminuria and microinflammation in chronic kidney disease. PLoS One. 2013;8:e54668. https://doi.org/10.1371/journal.pone.0054668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tsai YC, et al. Association of angiopoietin-2 with renal outcome in chronic kidney disease. PLoS One. 2014;9:e108862. https://doi.org/10.1371/journal.pone.0108862.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Tsai YC, et al. Angiopoietin-2, angiopoietin-1 and subclinical cardiovascular disease in chronic kidney disease. Sci Rep. 2016;6:39400. https://doi.org/10.1038/srep39400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fujisawa T, et al. Angiopoietin-1 promotes atherosclerosis by increasing the proportion of circulating Gr1+ monocytes. Cardiovasc Res. 2017;113:81–9. https://doi.org/10.1093/cvr/cvw223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yuan HT, Tipping PG, Li XZ, Long DA, Woolf AS. Angiopoietin correlates with glomerular capillary loss in anti-glomerular basement membrane glomerulonephritis. Kidney Int. 2002;61:2078–89. https://doi.org/10.1046/j.1523-1755.2002.00381.x.

    Article  CAS  PubMed  Google Scholar 

  67. Kim W, et al. COMP-angiopoietin-1 ameliorates renal fibrosis in a unilateral ureteral obstruction model. J Am Soc Nephrol. 2006;17:2474–83. https://doi.org/10.1681/asn.2006020109.

    Article  CAS  PubMed  Google Scholar 

  68. Dessapt-Baradez C, et al. Targeted glomerular angiopoietin-1 therapy for early diabetic kidney disease. J Am Soc Nephrol. 2014;25:33–42. https://doi.org/10.1681/asn.2012121218.

    Article  CAS  PubMed  Google Scholar 

  69. Singh S, et al. Tubular overexpression of angiopoietin-1 attenuates renal fibrosis. PLoS One. 2016;11:e0158908. https://doi.org/10.1371/journal.pone.0158908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Long DA, et al. Angiopoietin-1 therapy enhances fibrosis and inflammation following folic acid-induced acute renal injury. Kidney Int. 2008;74:300–9. https://doi.org/10.1038/ki.2008.179.

    Article  CAS  PubMed  Google Scholar 

  71. Ahmed A, et al. Angiopoietin-2 confers atheroprotection in apoE-/- mice by inhibiting LDL oxidation via nitric oxide. Circ Res. 2009;104:1333–6. https://doi.org/10.1161/circresaha.109.196154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Theelen TL, et al. Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice. Atherosclerosis. 2015;241:297–304. https://doi.org/10.1016/j.atherosclerosis.2015.05.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chang FC, et al. Angiopoietin-2-induced arterial stiffness in CKD. J Am Soc Nephrol. 2014;25:1198–209. https://doi.org/10.1681/asn.2013050542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hu J, et al. Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science. 2014;343:416–9. https://doi.org/10.1126/science.1244880.

    Article  CAS  PubMed  Google Scholar 

  75. Venkatesha S, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12:642–9. https://doi.org/10.1038/nm1429.

    Article  CAS  PubMed  Google Scholar 

  76. Leanos-Miranda A, Campos-Galicia I, Ramirez-Valenzuela KL, Chinolla-Arellano ZL, Isordia-Salas I. Circulating angiogenic factors and urinary prolactin as predictors of adverse outcomes in women with preeclampsia. Hypertension. 2013;61:1118–25. https://doi.org/10.1161/hypertensionaha.111.00754.

    Article  CAS  PubMed  Google Scholar 

  77. Shen F, et al. Endoglin deficiency impairs stroke recovery. Stroke. 2014;45:2101–6. https://doi.org/10.1161/strokeaha.114.005115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kapur NK, et al. Reducing endoglin activity limits calcineurin and TRPC-6 expression and improves survival in a mouse model of right ventricular pressure overload. J Am Heart Assoc. 2014;3:e000965. https://doi.org/10.1161/jaha.114.000965.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Ojeda-Fernandez L, et al. Mice lacking endoglin in macrophages show an impaired immune response. PLoS Genet. 2016;12:e1005935. https://doi.org/10.1371/journal.pgen.1005935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Charytan DM, et al. Circulating endoglin concentration is not elevated in chronic kidney disease. PLoS One. 2011;6:e23718. https://doi.org/10.1371/journal.pone.0023718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Docherty NG, et al. Endoglin regulates renal ischaemia-reperfusion injury. Nephrol Dial Transplant. 2006;21:2106–19. https://doi.org/10.1093/ndt/gfl179.

    Article  CAS  PubMed  Google Scholar 

  82. Oujo B, et al. L-Endoglin overexpression increases renal fibrosis after unilateral ureteral obstruction. PLoS One. 2014;9:e110365. https://doi.org/10.1371/journal.pone.0110365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Munoz-Felix JM, et al. Overexpression of the short endoglin isoform reduces renal fibrosis and inflammation after unilateral ureteral obstruction. Biochim Biophys Acta. 2016;1862:1801–14. https://doi.org/10.1016/j.bbadis.2016.06.010.

    Article  CAS  PubMed  Google Scholar 

  84. Siebert J, et al. Low serum angiogenin concentrations in patients with type 2 diabetes. Diabetes Care. 2007;30:3086–7. https://doi.org/10.2337/dc07-0629.

    Article  CAS  PubMed  Google Scholar 

  85. Nakamura M, et al. Hypoxic conditions stimulate the production of angiogenin and vascular endothelial growth factor by human renal proximal tubular epithelial cells in culture. Nephrol Dial Transplant. 2006;21:1489–95. https://doi.org/10.1093/ndt/gfl041.

    Article  CAS  PubMed  Google Scholar 

  86. Tavernier Q, et al. Urinary angiogenin reflects the magnitude of kidney injury at the infrahistologic level. J Am Soc Nephrol. 2017;28:678–90. https://doi.org/10.1681/asn.2016020218.

    Article  CAS  PubMed  Google Scholar 

  87. Mami I, et al. Angiogenin mediates cell-autonomous translational control under endoplasmic reticulum stress and attenuates kidney injury. J Am Soc Nephrol. 2016;27:863–76. https://doi.org/10.1681/asn.2015020196.

    Article  CAS  PubMed  Google Scholar 

  88. Saxena SK, Rybak SM, Davey RT Jr, Youle RJ, Ackerman EJ. Angiogenin is a cytotoxic, tRNA-specific ribonuclease in the RNase A superfamily. J Biol Chem. 1992;267:21982–6.

    CAS  PubMed  Google Scholar 

  89. Crawford SE, et al. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell. 1998;93:1159–70.

    Article  CAS  Google Scholar 

  90. Bige N, et al. Thrombospondin-1 plays a profibrotic and pro-inflammatory role during ureteric obstruction. Kidney Int. 2012;81:1226–38. https://doi.org/10.1038/ki.2012.21.

    Article  CAS  PubMed  Google Scholar 

  91. Cui W, Maimaitiyiming H, Qi X, Norman H, Wang S. Thrombospondin 1 mediates renal dysfunction in a mouse model of high-fat diet-induced obesity. Am J Physiol Renal Physiol. 2013;305:F871–80. https://doi.org/10.1152/ajprenal.00209.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zeisberg M, et al. Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure. Am J Pathol. 2014;184:2687–98. https://doi.org/10.1016/j.ajpath.2014.06.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Maimaitiyiming H, Zhou Q, Wang S. Thrombospondin 1 deficiency ameliorates the development of adriamycin-induced proteinuric kidney disease. PLoS One. 2016;11:e0156144. https://doi.org/10.1371/journal.pone.0156144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Maimaitiyiming H, Clemons K, Zhou Q, Norman H, Wang S. Thrombospondin1 deficiency attenuates obesity-associated microvascular complications in ApoE-/- mice. PLoS One. 2015;10:e0121403. https://doi.org/10.1371/journal.pone.0121403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yao M, et al. Thrombospondin-1 activation of signal-regulatory protein-alpha stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury. J Am Soc Nephrol. 2014;25:1171–86. https://doi.org/10.1681/asn.2013040433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sun D, et al. Thrombospondin-1 short hairpin RNA suppresses tubulointerstitial fibrosis in the kidney of ureteral obstruction by ameliorating peritubular capillary injury. Kidney Blood Press Res. 2012;35:35–47. https://doi.org/10.1159/000330718.

    Article  CAS  PubMed  Google Scholar 

  97. Hirakawa Y, et al. Quantitating intracellular oxygen tension in vivo by phosphorescence lifetime measurement. Sci Rep. 2015;5:17838. https://doi.org/10.1038/srep17838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tsubakihara Y, et al. High target hemoglobin with erythropoiesis-stimulating agents has advantages in the renal function of non-dialysis chronic kidney disease patients. Ther Apher Dial. 2012;16:529–40. https://doi.org/10.1111/j.1744-9987.2012.01082.x.

    Article  CAS  PubMed  Google Scholar 

  99. Palmer SC, et al. Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010;153:23–33. https://doi.org/10.7326/0003-4819-153-1-201007060-00252.

    Article  PubMed  Google Scholar 

  100. Mimura I, Tanaka T, Nangaku M. How the target hemoglobin of renal anemia should be. Nephron. 2015;131:202–9. https://doi.org/10.1159/000440849.

    Article  CAS  PubMed  Google Scholar 

  101. Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC. Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int. 2004;66:753–60. https://doi.org/10.1111/j.1523-1755.2004.00797.x.

    Article  PubMed  Google Scholar 

  102. Akizawa T, et al. A prospective observational study of early intervention with erythropoietin therapy and renal survival in non-dialysis chronic kidney disease patients with anemia: JET-STREAM study. Clin Exp Nephrol. 2016;20:885–95. https://doi.org/10.1007/s10157-015-1225-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Brines M, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A. 2004;101:14907–12. https://doi.org/10.1073/pnas.0406491101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Luks AM, Johnson RJ, Swenson ER. Chronic kidney disease at high altitude. J Am Soc Nephrol. 2008;19:2262–71. https://doi.org/10.1681/asn.2007111199.

    Article  CAS  PubMed  Google Scholar 

  105. Chen W, et al. Prevalence and risk factors of chronic kidney disease: a population study in the Tibetan population. Nephrol Dial Transplant. 2011;26:1592–9. https://doi.org/10.1093/ndt/gfq608.

    Article  PubMed  Google Scholar 

  106. Nicholl DD, et al. Declining kidney function increases the prevalence of sleep apnea and nocturnal hypoxia. Chest. 2012;141:1422–30. https://doi.org/10.1378/chest.11-1809.

    Article  PubMed  Google Scholar 

  107. Iseki K, Tohyama K, Matsumoto T, Nakamura H. High prevalence of chronic kidney disease among patients with sleep related breathing disorder (SRBD). Hypertens Res. 2008;31:249–55. https://doi.org/10.1291/hypres.31.249.

    Article  CAS  PubMed  Google Scholar 

  108. Chen CY, Liao KM. Chronic obstructive pulmonary disease is associated with risk of chronic kidney disease: a nationwide case-cohort study. Sci Rep. 2016;6:25855. https://doi.org/10.1038/srep25855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Prasad PV, Edelman RR, Epstein FH. Noninvasive evaluation of intrarenal oxygenation with BOLD MRI. Circulation. 1996;94:3271–5.

    Article  CAS  Google Scholar 

  110. Inoue T, et al. Noninvasive evaluation of kidney hypoxia and fibrosis using magnetic resonance imaging. J Am Soc Nephrol. 2011;22:1429–34. https://doi.org/10.1681/asn.2010111143.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Michaely HJ, et al. Renal BOLD-MRI does not reflect renal function in chronic kidney disease. Kidney Int. 2012;81:684–9. https://doi.org/10.1038/ki.2011.455.

    Article  CAS  PubMed  Google Scholar 

  112. Khatir DS, Pedersen M, Jespersen B, Buus NH. Evaluation of renal blood flow and oxygenation in CKD using magnetic resonance imaging. Am J Kidney Dis. 2015;66:402–11. https://doi.org/10.1053/j.ajkd.2014.11.022.

    Article  PubMed  Google Scholar 

  113. Pruijm M, et al. Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans. PLoS One. 2014;9:e95895. https://doi.org/10.1371/journal.pone.0095895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Piskunowicz M, et al. A new technique with high reproducibility to estimate renal oxygenation using BOLD-MRI in chronic kidney disease. Magn Reson Imaging. 2015;33:253–61. https://doi.org/10.1016/j.mri.2014.12.002.

    Article  PubMed  Google Scholar 

  115. Milani B, et al. Reduction of cortical oxygenation in chronic kidney disease: evidence obtained with a new analysis method of blood oxygenation level-dependent magnetic resonance imaging. Nephrol Dial Transplant. 2016; https://doi.org/10.1093/ndt/gfw362.

  116. Pruijm M, Milani B, Burnier M. Blood oxygenation level-dependent MRI to assess renal oxygenation in renal diseases: progresses and challenges. Front Physiol. 2016;7:667. https://doi.org/10.3389/fphys.2016.00667.

    Article  PubMed  Google Scholar 

  117. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12:5447–54.

    Article  CAS  Google Scholar 

  118. Rosenberger C, et al. Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. J Am Soc Nephrol. 2002;13:1721–32.

    Article  CAS  Google Scholar 

  119. Manotham K, et al. A biologic role of HIF-1 in the renal medulla. Kidney Int. 2005;67:1428–39. https://doi.org/10.1111/j.1523-1755.2005.00220.x.

    Article  CAS  PubMed  Google Scholar 

  120. Mimura I, et al. Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol Cell Biol. 2012;32:3018–32. https://doi.org/10.1128/mcb.06643-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nordquist L, et al. Activation of hypoxia-inducible factors prevents diabetic nephropathy. J Am Soc Nephrol. 2015;26:328–38. https://doi.org/10.1681/asn.2013090990.

    Article  PubMed  Google Scholar 

  122. Tanaka T, et al. Induction of protective genes by cobalt ameliorates tubulointerstitial injury in the progressive Thy1 nephritis. Kidney Int. 2005;68:2714–25. https://doi.org/10.1111/j.1523-1755.2005.00742.x.

    Article  CAS  PubMed  Google Scholar 

  123. Mack M, Yanagita M. Origin of myofibroblasts and cellular events triggering fibrosis. Kidney Int. 2015;87:297–307. https://doi.org/10.1038/ki.2014.287.

    Article  PubMed  Google Scholar 

  124. Yamazaki S, et al. A mouse model of adult-onset anaemia due to erythropoietin deficiency. Nat Commun. 2013;4:1950. https://doi.org/10.1038/ncomms2950.

    Article  CAS  PubMed  Google Scholar 

  125. Souma T, et al. Plasticity of renal erythropoietin-producing cells governs fibrosis. J Am Soc Nephrol. 2013;24:1599–616. https://doi.org/10.1681/asn.2013010030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Souma T, et al. Erythropoietin synthesis in renal myofibroblasts is restored by activation of hypoxia signaling. J Am Soc Nephrol. 2016;27:428–38. https://doi.org/10.1681/asn.2014121184.

    Article  CAS  PubMed  Google Scholar 

  127. Kawakami T, Mimura I, Shoji K, Tanaka T, Nangaku M. Kidney Int Suppl (2011). 2014;4:107–12.

    Article  CAS  Google Scholar 

  128. Humphreys BD, et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol. 2010;176:85–97. https://doi.org/10.2353/ajpath.2010.090517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gomez IG, et al. TWEAK-Fn14 signaling activates myofibroblasts to drive progression of fibrotic kidney disease. J Am Soc Nephrol. 2016;27:3639–52. https://doi.org/10.1681/asn.2015111227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lin SL, et al. Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am J Pathol. 2011;178:911–23. https://doi.org/10.1016/j.ajpath.2010.10.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Leaf IA, et al. Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury. J Clin Invest. 2017;127:321–34. https://doi.org/10.1172/jci87532.

    Article  PubMed  Google Scholar 

  132. Schrimpf C, et al. Pericyte TIMP3 and ADAMTS1 modulate vascular stability after kidney injury. J Am Soc Nephrol. 2012;23:868–83. https://doi.org/10.1681/asn.2011080851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kramann R, Wongboonsin J, Chang-Panesso M, Machado FG, Humphreys BD. Gli1+ pericyte loss induces capillary rarefaction and proximal tubular injury. J Am Soc Nephrol. 2017;28:776–84. https://doi.org/10.1681/asn.2016030297.

    Article  PubMed  Google Scholar 

  134. Manotham K, et al. Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int. 2004;65:871–80. https://doi.org/10.1111/j.1523-1755.2004.00461.x.

    Article  PubMed  Google Scholar 

  135. Lovisa S, et al. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med. 2015;21:998–1009. https://doi.org/10.1038/nm.3902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Grande MT, et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med. 2015;21:989–97. https://doi.org/10.1038/nm.3901.

    Article  CAS  PubMed  Google Scholar 

  137. Sun S, et al. Hypoxia-inducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition. Kidney Int. 2009;75:1278–87. https://doi.org/10.1038/ki.2009.62.

    Article  CAS  PubMed  Google Scholar 

  138. Du R, et al. Hypoxia-induced down-regulation of microRNA-34a promotes EMT by targeting the Notch signaling pathway in tubular epithelial cells. PLoS One. 2012;7:e30771. https://doi.org/10.1371/journal.pone.0030771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. LeBleu VS, et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med. 2013;19:1047–53. https://doi.org/10.1038/nm.3218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kang DH, Hughes J, Mazzali M, Schreiner GF, Johnson RJ. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol. 2001;12:1448–57.

    CAS  PubMed  Google Scholar 

  141. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18:4–25. https://doi.org/10.1210/edrv.18.1.0287.

    Article  CAS  PubMed  Google Scholar 

  142. Kim YG, et al. Vascular endothelial growth factor accelerates renal recovery in experimental thrombotic microangiopathy. Kidney Int. 2000;58:2390–9. https://doi.org/10.1046/j.1523-1755.2000.00422.x.

    Article  CAS  PubMed  Google Scholar 

  143. Leonard EC, Friedrich JL, Basile DP. VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury. Am J Physiol Renal Physiol. 2008;295:F1648–57. https://doi.org/10.1152/ajprenal.00099.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Basile DP, et al. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. Am J Physiol Renal Physiol. 2011;300:F721–33. https://doi.org/10.1152/ajprenal.00546.2010.

    Article  CAS  PubMed  Google Scholar 

  145. Iliescu R, Fernandez SR, Kelsen S, Maric C, Chade AR. Role of renal microcirculation in experimental renovascular disease. Nephrol Dial Transplant. 2010;25:1079–87. https://doi.org/10.1093/ndt/gfp605.

    Article  CAS  PubMed  Google Scholar 

  146. Chade AR, Tullos NA, Harvey TW, Mahdi F, Bidwell GL 3rd. Renal therapeutic angiogenesis using a bioengineered polymer-stabilized vascular endothelial growth factor construct. J Am Soc Nephrol. 2016;27:1741–52. https://doi.org/10.1681/asn.2015040346.

    Article  CAS  PubMed  Google Scholar 

  147. Ostendorf T, et al. VEGF(165) mediates glomerular endothelial repair. J Clin Invest. 1999;104:913–23. https://doi.org/10.1172/jci6740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Masuda Y, et al. Vascular endothelial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis. Am J Pathol. 2001;159:599–608. https://doi.org/10.1016/s0002-9440(10)61731-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Shimizu A, et al. Vascular endothelial growth factor165 resolves glomerular inflammation and accelerates glomerular capillary repair in rat anti-glomerular basement membrane glomerulonephritis. J Am Soc Nephrol. 2004;15:2655–65. https://doi.org/10.1097/01.asn.0000141038.28733.f2.

    Article  CAS  PubMed  Google Scholar 

  150. Woolard J, et al. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res. 2004;64:7822–35. https://doi.org/10.1158/0008-5472.can-04-0934.

    Article  CAS  PubMed  Google Scholar 

  151. Schumacher VA, et al. Impaired glomerular maturation and lack of VEGF165b in Denys-Drash syndrome. J Am Soc Nephrol. 2007;18:719–29. https://doi.org/10.1681/asn.2006020124.

    Article  CAS  PubMed  Google Scholar 

  152. Qiu Y, et al. Overexpression of VEGF165b in podocytes reduces glomerular permeability. J Am Soc Nephrol. 2010;21:1498–509. https://doi.org/10.1681/asn.2009060617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Tanaka T. Expanding roles of the hypoxia-response network in chronic kidney disease. Clin Exp Nephrol. 2016;20:835–44. https://doi.org/10.1007/s10157-016-1241-4.

    Article  CAS  PubMed  Google Scholar 

  154. Tanaka T, et al. Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model. Lab Investig. 2005;85:1292–307. https://doi.org/10.1038/labinvest.3700328.

    Article  CAS  PubMed  Google Scholar 

  155. Maxwell PH, Eckardt KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol. 2016;12:157–68. https://doi.org/10.1038/nrneph.2015.193.

    Article  CAS  PubMed  Google Scholar 

  156. Kushida N, et al. Hypoxia-inducible factor-1alpha activates the transforming growth factor-beta/SMAD3 pathway in kidney tubular epithelial cells. Am J Nephrol. 2016;44:276–85. https://doi.org/10.1159/000449323.

    Article  CAS  PubMed  Google Scholar 

  157. Basu RK, et al. Interdependence of HIF-1alpha and TGF-beta/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression. Am J Physiol Renal Physiol. 2011;300:F898–905. https://doi.org/10.1152/ajprenal.00335.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Rozen-Zvi B, et al. TGF-beta/Smad3 activates mammalian target of rapamycin complex-1 to promote collagen production by increasing HIF-1alpha expression. Am J Physiol Renal Physiol. 2013;305:F485–94. https://doi.org/10.1152/ajprenal.00215.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Higgins DF, et al. Hypoxic induction of Ctgf is directly mediated by Hif-1. Am J Physiol Renal Physiol. 2004;287:F1223–32. https://doi.org/10.1152/ajprenal.00245.2004.

    Article  CAS  PubMed  Google Scholar 

  160. Kroening S, Neubauer E, Wessel J, Wiesener M, Goppelt-Struebe M. Hypoxia interferes with connective tissue growth factor (CTGF) gene expression in human proximal tubular cell lines. Nephrol Dial Transplant. 2009;24:3319–25. https://doi.org/10.1093/ndt/gfp305.

    Article  CAS  PubMed  Google Scholar 

  161. Kimura K, et al. Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Renal Physiol. 2008;295:F1023–9. https://doi.org/10.1152/ajprenal.90209.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Higgins DF, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 2007;117:3810–20. https://doi.org/10.1172/jci30487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Yu X, et al. The balance of beneficial and deleterious effects of hypoxia-inducible factor activation by prolyl hydroxylase inhibitor in rat remnant kidney depends on the timing of administration. Nephrol Dial Transplant. 2012;27:3110–9. https://doi.org/10.1093/ndt/gfr754.

    Article  CAS  PubMed  Google Scholar 

  164. Hill JM, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:593–600. https://doi.org/10.1056/NEJMoa022287.

    Article  PubMed  Google Scholar 

  165. Krenning G, et al. Endothelial progenitor cell dysfunction in patients with progressive chronic kidney disease. Am J Physiol Renal Physiol. 2009;296:F1314–22. https://doi.org/10.1152/ajprenal.90755.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. de Groot K, et al. Uremia causes endothelial progenitor cell deficiency. Kidney Int. 2004;66:641–6. https://doi.org/10.1111/j.1523-1755.2004.00784.x.

    Article  PubMed  Google Scholar 

  167. Hung SC, et al. Indoxyl sulfate suppresses endothelial progenitor cell-mediated neovascularization. Kidney Int. 2016;89:574–85. https://doi.org/10.1016/j.kint.2015.11.020.

    Article  CAS  PubMed  Google Scholar 

  168. Chade AR, et al. Endothelial progenitor cells restore renal function in chronic experimental renovascular disease. Circulation. 2009;119:547–57. https://doi.org/10.1161/circulationaha.108.788653.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Huang TH, et al. Peripheral blood-derived endothelial progenitor cell therapy prevented deterioration of chronic kidney disease in rats. Am J Transl Res. 2015;7:804–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Goligorsky MS, Yasuda K, Ratliff B. Dysfunctional endothelial progenitor cells in chronic kidney disease. J Am Soc Nephrol. 2010;21:911–9. https://doi.org/10.1681/asn.2009111119.

    Article  CAS  PubMed  Google Scholar 

  171. Anglani F, et al. In search of adult renal stem cells. J Cell Mol Med. 2004;8:474–87.

    Article  CAS  Google Scholar 

  172. Tanaka S, Tanaka T, Nangaku M. Hypoxia and dysregulated angiogenesis in kidney disease. Kidney Dis (Basel). 2015;1:80–9. https://doi.org/10.1159/000381515.

    Article  Google Scholar 

  173. Kunter U, et al. Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipocytes. J Am Soc Nephrol. 2007;18:1754–64. https://doi.org/10.1681/asn.2007010044.

    Article  CAS  PubMed  Google Scholar 

  174. Kramann R, et al. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell. 2015;16:51–66. https://doi.org/10.1016/j.stem.2014.11.004.

    Article  CAS  PubMed  Google Scholar 

  175. Gregorini M, et al. Mesenchymal stromal cells prevent renal fibrosis in a rat model of unilateral ureteral obstruction by suppressing the renin-angiotensin system via HuR. PLoS One. 2016;11:e0148542. https://doi.org/10.1371/journal.pone.0148542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Huuskes BM, et al. Combination therapy of mesenchymal stem cells and serelaxin effectively attenuates renal fibrosis in obstructive nephropathy. FASEB J. 2015;29:540–53. https://doi.org/10.1096/fj.14-254789.

    Article  CAS  PubMed  Google Scholar 

  177. Eirin A, et al. Adipose tissue-derived mesenchymal stem cells improve revascularization outcomes to restore renal function in swine atherosclerotic renal artery stenosis. Stem Cells. 2012;30:1030–41. https://doi.org/10.1002/stem.1047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Zhu XY, et al. Mesenchymal stem cells and endothelial progenitor cells decrease renal injury in experimental swine renal artery stenosis through different mechanisms. Stem Cells. 2013;31:117–25. https://doi.org/10.1002/stem.1263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Imberti B, et al. Renal progenitors derived from human iPSCs engraft and restore function in a mouse model of acute kidney injury. Sci Rep. 2015;5:8826. https://doi.org/10.1038/srep08826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Toyohara T, et al. Cell therapy using human induced pluripotent stem cell-derived renal progenitors ameliorates acute kidney injury in mice. Stem Cells Transl Med. 2015;4:980–92. https://doi.org/10.5966/sctm.2014-0219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Chiang CK, Tanaka T, Inagi R, Fujita T, Nangaku M. Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner. Lab Investig. 2011;91:1564–71. https://doi.org/10.1038/labinvest.2011.114.

    Article  CAS  PubMed  Google Scholar 

  182. Asai H, et al. Activation of aryl hydrocarbon receptor mediates suppression of hypoxia-inducible factor-dependent erythropoietin expression by indoxyl sulfate. Am J Physiol Cell Physiol. 2016;310:C142–50. https://doi.org/10.1152/ajpcell.00172.2015.

    Article  PubMed  Google Scholar 

  183. Tanaka T, Yamaguchi J, Higashijima Y, Nangaku M. Indoxyl sulfate signals for rapid mRNA stabilization of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) and suppresses the expression of hypoxia-inducible genes in experimental CKD and uremia. FASEB J. 2013;27:4059–75. https://doi.org/10.1096/fj.13-231837.

    Article  CAS  PubMed  Google Scholar 

  184. Palm F, et al. Uremia induces abnormal oxygen consumption in tubules and aggravates chronic hypoxia of the kidney via oxidative stress. Am J Physiol Renal Physiol. 2010;299:F380–6. https://doi.org/10.1152/ajprenal.00175.2010.

    Article  CAS  PubMed  Google Scholar 

  185. Yamaguchi J, Tanaka T, Inagi R. Effect of AST-120 in chronic kidney disease treatment: still a controversy? Nephron. 2017;135:201–6. https://doi.org/10.1159/000453673.

    Article  CAS  PubMed  Google Scholar 

  186. Akizawa T, et al. Effect of a carbonaceous oral adsorbent on the progression of CKD: a multicenter, randomized, controlled trial. Am J Kidney Dis. 2009;54:459–67. https://doi.org/10.1053/j.ajkd.2009.05.011.

    Article  CAS  PubMed  Google Scholar 

  187. Schulman G, et al. Randomized placebo-controlled EPPIC trials of AST-120 in CKD. J Am Soc Nephrol. 2015;26:1732–46. https://doi.org/10.1681/asn.2014010042.

    Article  CAS  PubMed  Google Scholar 

  188. Schulman G, et al. The effects of AST-120 on chronic kidney disease progression in the United States of America: a post hoc subgroup analysis of randomized controlled trials. BMC Nephrol. 2016;17:141. https://doi.org/10.1186/s12882-016-0357-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Cha RH, et al. A randomized, controlled trial of oral intestinal sorbent AST-120 on renal function deterioration in patients with advanced renal dysfunction. Clin J Am Soc Nephrol. 2016;11:559–67. https://doi.org/10.2215/cjn.12011214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Chiang CK, Nangaku M, Tanaka T, Iwawaki T, Inagi R. Endoplasmic reticulum stress signal impairs erythropoietin production: a role for ATF4. Am J Physiol Cell Physiol. 2013;304:C342–53. https://doi.org/10.1152/ajpcell.00153.2012.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Nephrology and Endocrinology, The University of Tokyo School of Medicine, Tokyo, Japan

    Yosuke Hirakawa, Tetsuhiro Tanaka & Masaomi Nangaku

Authors
  1. Yosuke Hirakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tetsuhiro Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masaomi Nangaku
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masaomi Nangaku .

Editor information

Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, Indiana Center for Musculoskeletal Health, Indianapolis, IN, USA

    Monte S. Willis

  2. Department of Health Promotion and Development, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Nursing, Pittsburgh, PA, USA

    Cecelia C. Yates

  3. Department of Pharmacology and Department of Pathology and Lab Medicine, McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jonathan C. Schisler

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hirakawa, Y., Tanaka, T., Nangaku, M. (2019). Tipping the Balance from Angiogenesis to Fibrosis in Chronic Kidney Disease. In: Willis, M., Yates, C., Schisler, J. (eds) Fibrosis in Disease . Molecular and Translational Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-98143-7_16

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-98143-7_16

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-98142-0

  • Online ISBN: 978-3-319-98143-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation