Hypoxia and Renal Tubulointerstitial Fibrosis

  • Zuo-Lin Li
  • Bi-Cheng LiuEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1165)


Hypoxia, one of the most common causes of kidney injury, is a key pathological condition in various kidney diseases. Renal fibrosis is the terminal pathway involved in the continuous progression of chronic kidney disease (CKD), characterized by glomerulosclerosis and tubulointerstitial fibrosis (TIF). Recent studies have shown that hypoxia is a key factor promoting the progression of TIF. Loss of microvasculature, reduced oxygen dispersion, and metabolic abnormality of cells in the kidney are the main causes of the hypoxic state. Hypoxia can, in turn, profoundly affect the tubular epithelial cells, endothelial cells, pericytes, fibroblasts, inflammatory cells, and progenitor cells. In this chapter, we reviewed the critical roles of hypoxia in the pathophysiology of TIF and discussed the potential of anti-hypoxia as its promising therapeutic target.


Hypoxia Tubulointerstitial fibrosis Hypoxia-inducible factor 



This study was supported by grants from the National Key Research and Development Program of China (2018YFC1314004) and the National Natural Scientific Foundation (No. 81720108007, 81130010, 81470997 and 81670696), the Clinic Research Center of Jiangsu Province (No. BL2014080) to Professor Bi-Cheng Liu as PI.


  1. Abdelkader A, Ho J, Ow CP, Eppel GA, Rajapakse NW, Schlaich MP, Evans RG (2014) Renal oxygenation in acute renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 306:F1026–F1038PubMedCrossRefGoogle Scholar
  2. Asada N, Takase M, Nakamura J, Oguchi A, Asada M, Suzuki N, Yamamura K, Nagoshi N, Shibata S, Rao TN, Fehling HJ, Fukatsu A, Minegishi N, Kita T, Kimura T, Okano H, Yamamoto M, Yanagita M (2011) Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. J Clin Invest 121:3981–3990PubMedPubMedCentralCrossRefGoogle Scholar
  3. Baumann B, Hayashida T, Liang X, Schnaper HW (2016) Hypoxia-inducible factor-1α promotes glomerulosclerosis and regulates COL1A2 expression through interactions with Smad3. Kidney Int 90:797–808PubMedPubMedCentralCrossRefGoogle Scholar
  4. Blantz RC, Deng A, Miracle CM, Thomson SC (2007) Regulation of kidney function and metabolism: a question of supply and demand. Trans Am Clin Climatol Assoc 118:23–43PubMedPubMedCentralGoogle Scholar
  5. Bonomini M, Del Vecchio L, Sirolli V, Locatelli F (2016) New treatment approaches for the anemia of CKD. Am J Kidney Dis 67:133–142PubMedCrossRefPubMedCentralGoogle Scholar
  6. Bonventre JV, Yang L (2011) Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 121:4210–4221PubMedPubMedCentralCrossRefGoogle Scholar
  7. Carlström M, Wilcox CS, Arendshorst WJ (2015) Renal autoregulation in health and disease. Physiol Rev 95:405–511PubMedPubMedCentralCrossRefGoogle Scholar
  8. Calzavacca P, Evans RG, Bailey M, Bellomo R, May CN (2015) Cortical and medullary tissue perfusion and oxygenation in experimental septic acute kidney injury. Crit Care Med 43:e431–e439PubMedCrossRefPubMedCentralGoogle Scholar
  9. Ceradini DJ, Gurtner GC (2005) Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue. Trends Cardiovasc Med 15:57–63PubMedCrossRefPubMedCentralGoogle Scholar
  10. Davidson A (2016) What is damaging the kidney in lupus nephritis? Nat Rev Rheumatol 12:143–153PubMedCrossRefPubMedCentralGoogle Scholar
  11. Davis MJHM, Kuo L (2008) Local regulation of microvascular perfusion. In: Tuma RFDW, Ley K (eds). Handbook of physiology: microcirculation, 2nd edn. Elsevier, San Diego, CACrossRefGoogle Scholar
  12. Deng W, Ren Y, Feng X, Yao G, Chen W, Sun Y, Wang H, Gao X, Sun L (2014) Hypoxia inducible factor-1 alpha promotes mesangial cell proliferation in lupus nephritis. Am J Nephrol 40:507–515PubMedCrossRefPubMedCentralGoogle Scholar
  13. 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 tumour suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. Nat Med 12:1081–1087PubMedCrossRefPubMedCentralGoogle Scholar
  14. Eckardt KU, Rosenberger C, Jurgensen JS, Wiesener MS (2003) Role of hypoxia in the pathogenesis of renal disease. Blood Purif 21:253–257PubMedCrossRefPubMedCentralGoogle Scholar
  15. Edeling M, Ragi G, Huang S, Pavenstädt H, Susztak K (2016) Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog. Nat Rev Nephrol 12:426–439PubMedPubMedCentralCrossRefGoogle Scholar
  16. Efrati S, Berman S, Hamad RA, Siman-Tov Y, Ilgiyaev E, Maslyakov I, Weissgarten J (2012) Effect of captopril treatment on recuperation from ischemia/reperfusion-induced acute renal injury. Nephrol Dial Transplant 27:136–145PubMedCrossRefPubMedCentralGoogle Scholar
  17. Emans TW, Janssen BJ, Pinkham MI, Ow CP, Evans RG, Joles JA, Malpas SC, Krediet CT, Koeners MP (2016) Exogenous and endogenous angiotensin-II decrease renal cortical oxygen tension in conscious rats by limiting renal blood flow. J Physiol 594:6287–6300PubMedPubMedCentralCrossRefGoogle Scholar
  18. Evans RG, Eppel GA, Michaels S, Burke SL, Nematbakhsh M, Head GA, Carroll JF, O’Connor PM (2010) Multiple mechanisms act to maintain kidney oxygenation during renal ischemia in anesthetized rabbits. Am J Physiol Renal Physiol 298:F1235–F1243PubMedCrossRefPubMedCentralGoogle Scholar
  19. Evans RG, Gardiner BS, Smith DW, O’Connor PM (2008) Intrarenal oxygenation: unique challenges and the biophysical basis of homeostasis. Am J Physiol Renal Physiol 295:F1259–F1270PubMedCrossRefGoogle Scholar
  20. Fahling M, Seeliger E, Patzak A, Persson PB (2017) Understanding and preventing contrast-induced acute kidney injury. Nat Rev Nephrol 13:169–180PubMedCrossRefGoogle Scholar
  21. Falke LL, Gholizadeh S, Goldschmeding R, Kok RJ, Nguyen TQ (2015) Diverse origins of the myofibroblast-implications for kidney fibrosis. Nat Rev Nephrol 11:233–244PubMedCrossRefGoogle Scholar
  22. Fine LG, Orphanides C, Norman JT (1998) Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int 65(Suppl):S74–S78Google Scholar
  23. Gilkes DM, Bajpai S, Chaturvedi P, Wirtz D, Semenza GL (2013) Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J Biol Chem 288:10819–10829PubMedPubMedCentralCrossRefGoogle Scholar
  24. Haase VH (2013) Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev 27:41–53PubMedPubMedCentralCrossRefGoogle Scholar
  25. Haase VH (2017a) Oxygen sensors as therapeutic targets in kidney disease. Nephrol Ther 13(Suppl 1):S29–S34PubMedCrossRefPubMedCentralGoogle Scholar
  26. Haase VH (2017b) HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int 21(Suppl 1):S110–S124PubMedPubMedCentralCrossRefGoogle Scholar
  27. 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-tomesenchymal transition. J Clin Invest 117:3810–3820PubMedPubMedCentralGoogle Scholar
  28. Hill P, Shukla D, Tran MG, Aragones J, Cook HT, Carmeliet P, Maxwell PH (2008) Inhibition of hypoxia inducible hydroxylases protects against renal ischemia-reperfusion injury. J Am Soc Nephrol 19:39–46PubMedPubMedCentralCrossRefGoogle Scholar
  29. Holthoff JH, Wang Z, Seely KA, Gokden N, Mayeux PR (2012) Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury. Kidney Int 81:370–378PubMedCrossRefGoogle Scholar
  30. Huen SC, Cantley LG (2017) Macrophages in renal injury and repair. Annu Rev Physiol 79:449–469PubMedCrossRefGoogle Scholar
  31. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468PubMedCrossRefGoogle Scholar
  32. Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ (2002) Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 13:806–816PubMedCrossRefGoogle Scholar
  33. Kasztan M, Fox BM, Speed JS, De Miguel C, Gohar EY, Townes TM, Kutlar A, Pollock JS, Pollock DM (2017) Long-term Endothelin-A receptor antagonism provides robust renal protection in humanized sickle cell disease Mice. J Am Soc Nephrol 28:2443–2458PubMedPubMedCentralCrossRefGoogle Scholar
  34. Katavetin P, Inagi R, Miyata T, Tanaka T, Sassa R, Ingelfinger JR, Fujita T, Nangaku M (2008) Albumin suppresses vascular endothelial growth factor via alteration of hypoxia-inducible factor/hypoxia-responsive element pathway. Biochem Biophys Res Commun 367:305–310PubMedCrossRefGoogle Scholar
  35. Kim W, Moon SO, Lee SY, Jang KY, Cho CH, Koh GY, Choi KS, Yoon KH, Sung MJ, Kim DH, Lee S, Kang KP, Park SK (2006) COMP-angiopoietin-1 ameliorates renal fibrosis in a unilateral ureteral obstruction model. J Am Soc Nephrol 17:2474–2483PubMedCrossRefGoogle Scholar
  36. Kitching AR (2014) Dendritic cells in progressive renal disease: some answers, many questions. Nephrol Dial Transplant 29:2185–2193CrossRefGoogle Scholar
  37. Kramann R, Humphreys BD (2014) Kidney pericytes: roles in regeneration and fibrosis. Semin Nephrol 34:374–383PubMedPubMedCentralCrossRefGoogle Scholar
  38. Lameire NH, Bagga A, Cruz D, De Maeseneer J, Endre Z, Kellum JA, Liu KD, Mehta RL, Pannu N, Van Biesen W, Vanholder R (2013) Acute kidney injury: an increasing global concern. Lancet 382:170–179PubMedCrossRefGoogle Scholar
  39. Lannemyr L, Bragadottir G, Krumbholz V, Redfors B, Sellgren J, Ricksten SE (2017) Effects of cardiopulmonary bypass on renal perfusion, filtration, and oxygenation in patients undergoing cardiac surgery. Anesthesiology 126:205–213PubMedCrossRefPubMedCentralGoogle Scholar
  40. Layton AT, Laghmani K, Vallon V, Edwards A (2016) Solute transport and oxygen consumption along the nephrons: effects of Na+ transport inhibitors. Am J Physiol Renal Physiol 311:F1217–F1229PubMedPubMedCentralCrossRefGoogle Scholar
  41. Laycock SK, Vogel T, Forfia PR, Tuzman J, Xu X, Ochoa M, Thompson CI, Nasjletti A, Hintze TH (1998) Role of nitric oxide in the control of renal oxygen consumption and the regulation of chemical work in the kidney. Circ Res 82:1263–1271PubMedCrossRefPubMedCentralGoogle Scholar
  42. Leung KC, Tonelli M, James MT (2013) Chronic kidney disease following acute kidney injury-risk and outcomes. Nat Rev Nephrol 9:77–85CrossRefGoogle Scholar
  43. Li J, Qu X, Yao J, Caruana G, Ricardo SD, Yamamoto Y, Yamamoto H, Bertram JF (2010) Blockade of endothelial-mesenchymal transition by a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. Diabetes 59:2612–2624PubMedPubMedCentralCrossRefGoogle Scholar
  44. Li Y, Yang J, Dai C, Wu C, Liu Y (2003) Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J Clin Invest 112:503–516PubMedPubMedCentralCrossRefGoogle Scholar
  45. Lin SL, Chang FC, Schrimpf C, Chen YT, Wu CF, Wu VC, Chiang WC, Kuhnert F, Kuo CJ, Chen YM, Wu KD, Tsai TJ, Duffield JS (2011) Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am J Pathol 178:911–923PubMedPubMedCentralCrossRefGoogle Scholar
  46. Liu BC, Tang TT, Lv LL, Lan HY (2018) Renal tubule injury: a driving force toward chronic kidney disease. Kidney Int 93:568–579CrossRefPubMedPubMedCentralGoogle Scholar
  47. Lv LL, Tang PM, Li CJ, You YK, Li J, Huang XR, Ni J, Feng M, Liu BC, Lan HY (2017) The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation. Kidney Int 91:587–602PubMedCrossRefPubMedCentralGoogle Scholar
  48. Lv LL, Feng Y, Wen Y, Wu WJ, Ni HF, Li ZL, Zhou LT, Wang B, Zhang JD, Crowley SD, Liu BC (2018a) Exosomal CCL2 from tubular epithelial cells is critical for albumin-induced tubulointerstitial inflammation. J Am Soc Nephrol 29:919–935PubMedPubMedCentralGoogle Scholar
  49. Lv W, Booz GW, Wang Y, Fan F, Roman RJ (2018b) Inflammation and renal fibrosis: recent developments on key signaling molecules as potential therapeutic targets. Eur J Pharmacol 820:65–76PubMedCrossRefPubMedCentralGoogle Scholar
  50. Manotham K, Tanaka T, Matsumoto M, Ohse T, Inagi R, Miyata T, Kurokawa K, Fujita T, Ingelfinger JR, Nangaku M (2004) Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int 65:871–880PubMedCrossRefPubMedCentralGoogle Scholar
  51. Matsui T, Oda E, Higashimoto Y, Yamagishi S (2015) Glyceraldehyde-derived pyridinium (GLAP) evokes oxidative stress and inflammatory and thrombogenic reactions in endothelial cells via the interaction with RAGE. Cardiovasc Diabetol 14:1PubMedPubMedCentralCrossRefGoogle Scholar
  52. Mole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, Ratcliffe PJ (2009) Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. J Biol Chem 284:16767–16775PubMedPubMedCentralCrossRefGoogle Scholar
  53. Nangaku M, Rosenberger C, Heyman SN, Eckardt KU (2013) Regulation of hypoxia-inducible factor in kidney disease. Clin Exp Pharmacol Physiol 40:148–157PubMedCrossRefPubMedCentralGoogle Scholar
  54. Norman JT, Clark IM, Garcia PL (2000) Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int 58:2351–2366PubMedCrossRefPubMedCentralGoogle Scholar
  55. Ow CPC, Abdelkader A, Hilliard LM, Phillips JK, Evans RG (2014) Determinants of renal tissue hypoxia in a rat model of polycystic kidney disease. Am J Physiol Regul Integr Comp Physiol 307:R1207–R1215PubMedCrossRefPubMedCentralGoogle Scholar
  56. Paddenberg R, Faulhammer P, Goldenberg A, Kummer W (2006) Hypoxia-induced increase of endostatin in murine aorta and lung. Histochem Cell Biol 125:1–12CrossRefGoogle Scholar
  57. Palm F, Cederberg J, Hansell P, Liss P, Carlsson PO (2003) Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension. Diabetologia 46:1153–1160PubMedCrossRefPubMedCentralGoogle Scholar
  58. Parks SK, Chiche J, Pouyssegur J (2011) pH control mechanisms of tumor survival and growth. J Cell Physiol 226:299–308PubMedCrossRefPubMedCentralGoogle Scholar
  59. Pittman RN (2011) Regulation of tissue oxygenation, 1st edn. Morgan & Claypool Life Science, San RafaelGoogle Scholar
  60. Pruijm M, Milani B, Pivin E, Podhajska A, Vogt B, Stuber M, Burnier M (2018) Reduced cortical oxygenation predicts a progressive decline of renal function in patients with chronic kidney disease. Kidney Int 93:932–940PubMedCrossRefGoogle Scholar
  61. Priyadarshi A, Periyasamy S, Burke TJ, Britton SL, Malhortra D, Shapiro JI (2002) Effects of reduction of renal mass on renal oxygen tension and erythropoietin production in the rat. Kidney Int 61:542–546PubMedCrossRefGoogle Scholar
  62. Rama I, Bruene B, Torras J, Koehl R, Cruzado JM, Bestard O, Franquesa M, Lloberas N, Weigert A, Herrero-Fresneda I, Gulias O, Grinyó JM (2008) Hypoxia stimulus: an adaptive immune response during dendritic cell maturation. Kidney Int 73:816–825PubMedCrossRefGoogle Scholar
  63. Rewa O, Bagshaw SM (2014) Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol 10:193–207PubMedCrossRefGoogle Scholar
  64. Rosenberger C, Mandriota S, Jürgensen JS, Wiesener MS, Hörstrup 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 13:1721–1732PubMedCrossRefGoogle Scholar
  65. Schnaper HW (2017) The tubulointerstitial pathophysiology of progressive kidney disease. Adv Chronic Kidney Dis 24:107–116PubMedPubMedCentralCrossRefGoogle Scholar
  66. Schödel J, Klanke B, Weidemann A, Buchholz B, Bernhardt W, Bertog M, Amann K, Korbmacher C, Wiesener M, Warnecke C, Kurtz A, Eckardt KU, Willam C (2009) HIF-prolyl hydroxylases in the rat kidney: physiologic expression patterns and regulation in acute kidney injury. Am J Pathol 174:1663–1674PubMedPubMedCentralCrossRefGoogle Scholar
  67. Sgouralis I, Evans RG, Layton AT (2017) Renal medullary and urinary oxygen tension during cardiopulmonary bypass in the rat. Math Med Biol 34:313–333PubMedPubMedCentralGoogle Scholar
  68. Shi H, Yan T, Li D, Jia J, Shang W, Wei L, Zheng Z (2017) Detection of renal hypoxia in lupus nephritis using blood oxygen level-dependent MR imaging: a multiple correspondence analysis. Kidney Blood Press Res 42:123–135PubMedCrossRefPubMedCentralGoogle Scholar
  69. Singh P, Ricksten SE, Bragadottir G, Redfors B, Nordquist L (2013) Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease. Clin Exp Pharmacol Physiol 40:138–147PubMedPubMedCentralCrossRefGoogle Scholar
  70. Starling S (2017) Renal fibrosis: pericytes activate complement in fibrosis. Nat Rev Nephrol 13:262PubMedGoogle Scholar
  71. Stillman IE, Brezis M, Heyman SN, Epstein FH, Spokes K, Rosen S (1994) Effects of salt depletion on the kidney: changes in medullary oxygenation and thick ascending limb size. J Am Soc Nephrol 4:1538–1545PubMedGoogle Scholar
  72. Tanaka S, Tanaka T, Nangaku M (2014) Hypoxia as a key player in the AKI-to-CKD transition. Am J Physiol Renal Physiol 307:F1187–F1195PubMedCrossRefGoogle Scholar
  73. Tessari P (2015) Nitric oxide in the normal kidney and in patients with diabetic nephropathy. J Nephrol 28:257–268PubMedCrossRefGoogle Scholar
  74. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C, Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators (2005) Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294:813–818Google Scholar
  75. van der Bel R, Coolen BF, Nederveen AJ, Potters WV, Verberne HJ, Vogt L, Stroes ES, Krediet CT (2016) Magnetic resonance imaging-derived renal oxygenation and perfusion during continuous, steady-state Angiotensin-II infusion in healthy humans. J Am Heart Assoc 5:e003185PubMedPubMedCentralGoogle Scholar
  76. Wang Z, Holthoff JH, Seely KA, Pathak E, Spencer HJ 3rd, Gokden N, Mayeux PR (2012) Development of oxidative stress in the peritubular capillary microenvironment mediates sepsis-induced renal microcirculatory failure and acute kidney injury. Am J Pathol 180:505–516PubMedPubMedCentralCrossRefGoogle Scholar
  77. Webster AC, Nagler EV, Morton RL, Masson P (2017) Chronic kidney disease. Lancet 389(10075):1238–1252PubMedCrossRefGoogle Scholar
  78. Weinberg JM (2011) Mitochondrial biogenesis in kidney disease. J Am Soc Nephrol 22:431–436PubMedCrossRefGoogle Scholar
  79. Welch WJ, Baumgartl H, Lubbers D, Wilcox CS (2003) Renal oxygenation defects in the spontaneously hypertensive rat: role of AT1 receptors. Kidney Int 63:202–208PubMedCrossRefPubMedCentralGoogle Scholar
  80. Xavier S, Vasko R, Matsumoto K, Zullo JA, Chen R, Maizel J, Chander PN, Goligorsky MS (2015) Curtailing endothelial TGF-β signaling is sufficient to reduce endothelial-mesenchymal transition and fibrosis in CKD. J Am Soc Nephrol 26:817–829PubMedCrossRefPubMedCentralGoogle Scholar
  81. Xia Y, Yan J, Jin X, Entman ML, Wang Y (2014) The chemokine receptor CXCR82 contributes to recruitment of bone marrow-derived fibroblast precursors in renal fibrosis. Kidney Int 86:327–337PubMedPubMedCentralCrossRefGoogle Scholar
  82. Yin W, Liu F, Li X, Yang L, Zhao S, Huang ZX, Huang YQ, Liu RB (2012) Noninvasive evaluation of renal oxygenation in diabetic nephropathy by BOLD-MRI. Eur J Radiol 81:1426–1431PubMedCrossRefPubMedCentralGoogle Scholar
  83. Zhang Y, Wang J, Yang X, Wang X, Zhang J, Fang J, Jiang X (2012) The serial effect of iodinated contrast media on renal hemodynamics and oxygenation as evaluated by ASL and BOLD MRI. Contrast Media Mol Imaging 7:418–425PubMedCrossRefPubMedCentralGoogle Scholar
  84. Zhou D, Fu H, Zhang L, Zhang K, Min Y, Xiao L, Lin L, Bastacky SI, Liu Y (2017) Tubule-derived Wnts are required for fibroblast activation and kidney fibrosis. J Am Soc Nephrol 28:2322–2336PubMedPubMedCentralCrossRefGoogle Scholar
  85. Zhou D, Liu Y (2016) Renal fibrosis in 2015: understanding the mechanisms of kidney fibrosis. Nat Rev Nephrol 12:68–70PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Institute of Nephrology, Zhong Da HospitalSoutheast University School of MedicineNanjingChina

Personalised recommendations