Inflammatory Mediators and Renal Fibrosis

  • Xiao-Ming MengEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1165)


Renal inflammation is the initial, healthy response to renal injury. However, prolonged inflammation promotes the fibrosis process, which leads to chronic pathology and eventually end-stage kidney disease. There are two major sources of inflammatory cells: first, bone marrow-derived leukocytes that include neutrophils, macrophages, fibrocytes and mast cells, and second, locally activated kidney cells such as mesangial cells, podocytes, tubular epithelial cells, endothelial cells and fibroblasts. These activated cells produce many profibrotic cytokines and growth factors that cause accumulation and activation of myofibroblasts, and enhance the production of the extracellular matrix. In particular, activated macrophages are key mediators that drive acute inflammation into chronic kidney disease. They produce large amounts of profibrotic factors and modify the microenvironment via a paracrine effect, and they also transdifferentiate to myofibroblasts directly, although the origin of myofibroblasts in the fibrosing kidney remains controversial. Collectively, understanding inflammatory cell functions and mechanisms during renal fibrosis is paramount to improving diagnosis and treatment of chronic kidney disease.


Macrophage Renal fibrosis Myofibroblast TGF-β 



This laboratory is supported by grants from National Natural Science Foundation of China (National Science Foundation of China 81300580 and 81570623) and by Science and Technological Fund of Anhui Province for Outstanding Youth of China (Grant number: 1608085J07).


  1. Abboud HE (2012) Mesangial cell biology. Exp Cell Res 318:979–985Google Scholar
  2. Allison SJ (2013) Fibrosis: the source of myofibroblasts in kidney fibrosis. Nat Rev Nephrol 9:494PubMedGoogle Scholar
  3. Anders HJ, Ryu M (2011) Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int 80:915–925PubMedPubMedCentralCrossRefGoogle Scholar
  4. Anders HJ, Vielhauer V, Eis V, Linde Y, Kretzler M et al (2004) Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice. FASEB J 18:534–536PubMedCrossRefGoogle Scholar
  5. Beghdadi W, Madjene LC, Claver J, Pejler G, Beaudoin L, Lehuen A, Daugas E, Blank U (2013) Mast cell chymase protects against renal fibrosis in murine unilateral ureteral obstruction. Kidney Int 84:317–326PubMedCrossRefGoogle Scholar
  6. Bielesz B, Sirin Y, Si H, Niranjan T, Gruenwald A et al (2010) Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. J Clin Invest 120:4040–4054PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bojakowski K, Abramczyk P, Bojakowska M, Zwolinska A, Przybylski J, Gaciong Z (2001) Fucoidan improves the renal blood flow in the early stage of renal ischemia/reperfusion injury in the rat. J Physiol Pharmacol 52:137–143PubMedGoogle Scholar
  8. Boor P, Floege J (2011) Chronic kidney disease growth factors in renal fibrosis. Clin Exp Pharmacol Physiol 38:441–450PubMedCrossRefGoogle Scholar
  9. Boor P, Konieczny A, Villa L, Kunter U, van Roeyen CR et al (2007) PDGF-D inhibition by CR10 ameliorates tubulointerstitial fibrosis following experimental glomerulonephritis. Nephrol Dial Transplant 22:1323–1331PubMedCrossRefGoogle Scholar
  10. Boor P, Ostendorf T, Floege J (2010) Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat Rev Nephrol 6:643–656PubMedCrossRefGoogle Scholar
  11. Boor P, Ostendorf T, Floege J (2014) PDGF and the progression of renal disease. Nephrol Dial Transplant 29(Suppl 1):i45–i54PubMedCrossRefGoogle Scholar
  12. Boor P, Babickova J, Steegh F, Hautvast P, Martin IV et al (2015) Role of platelet-derived growth factor-CC in capillary rarefaction in renal fibrosis. Am J Pathol 185:2132–2142PubMedCrossRefGoogle Scholar
  13. Bottinger EP, Bitzer M (2002) TGF-beta signaling in renal disease. J Am Soc Nephrol 13:2600–2610PubMedPubMedCentralCrossRefGoogle Scholar
  14. Brahler S, Ising C, Hagmann H, Rasmus M, Hoehne M et al (2012) Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria. Am J Physiol Renal Physiol 303:F1473–F1485PubMedCrossRefGoogle Scholar
  15. Broekema M, Harmsen MC, van Luyn MJ, Koerts JA, Petersen AH et al (2007) Bone marrow-derived myofibroblasts contribute to the renal interstitial myofibroblast population and produce procollagen I after ischemia/reperfusion in rats. J Am Soc Nephrol 18:165–175PubMedPubMedCentralCrossRefGoogle Scholar
  16. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A (1994) Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1:71–81PubMedPubMedCentralCrossRefGoogle Scholar
  17. Buchtler S, Grill A, Hofmarksrichter S, Stockert P, Schiechl-Brachner G et al (2018) Cellular origin and functional relevance of collagen i production in the kidney. J Am Soc Nephrol 29:1859–1873PubMedPubMedCentralCrossRefGoogle Scholar
  18. Buhl EM, Djudjaj S, Babickova J, Klinkhammer BM, Folestad E et al (2016) The role of PDGF-D in healthy and fibrotic kidneys. Kidney Int 8:848–861CrossRefGoogle Scholar
  19. Campbell MT, Hile KL, Zhang H, Asanuma H, Vanderbrink BA et al (2011) Toll-like receptor 4: a novel signaling pathway during renal fibrogenesis. J Surg Res 168:e61–e69PubMedPubMedCentralCrossRefGoogle Scholar
  20. Canaud G, Bienaime F, Viau A, Treins C, Baron W et al (2013) AKT2 is essential to maintain podocyte viability and function during chronic kidney disease. Nat Med 19:1288–1296PubMedCrossRefGoogle Scholar
  21. Cao Q, Wang Y, Harris DC (2013) Pathogenic and protective role of macrophages in kidney disease. Am J Physiol Renal Physiol 305:F3–F11PubMedPubMedCentralCrossRefGoogle Scholar
  22. Chen G, Lin SC, Chen J, He L, Dong F et al (2011a) CXCL16 recruits bone marrow-derived fibroblast precursors in renal fibrosis. J Am Soc Nephrol 22:1876–1886PubMedPubMedCentralCrossRefGoogle Scholar
  23. Chen YT, Chang FC, Wu CF, Chou YH, Hsu HL et al (2011b) Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis. Kidney Int 80:1170–1181PubMedPubMedCentralCrossRefGoogle Scholar
  24. Chen J, Chen MX, Fogo AB, Harris RC, Chen JK (2013) mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking. J Am Soc Nephrol 24:198–207PubMedPubMedCentralCrossRefGoogle Scholar
  25. Chen G, Dong Z, Liu H, Liu Y, Duan S, Liu F, Chen H (2016) mTOR signaling regulates protective activity of transferred CD4+ Foxp3+ T Cells in repair of acute kidney injury. J Immunol 197:3917–3926PubMedCrossRefGoogle Scholar
  26. Cheng A, Dong Y, Zhu F, Liu Y, Hou FF, Nie J (2013) AGE-LDL activates Toll like receptor 4 pathway and promotes inflammatory cytokines production in renal tubular epithelial cells. Int J Biol Sci 9:94–107PubMedPubMedCentralCrossRefGoogle Scholar
  27. Chesney J, Metz C, Stavitsky AB, Bacher M, Bucala R (1998) Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. J Immunol 160:419–425PubMedGoogle Scholar
  28. Chung AC, Lan HY (2011) Chemokines in renal injury. J Am Soc Nephrol 22:802–809PubMedCrossRefGoogle Scholar
  29. Correa-Costa M, Braga TT, Semedo P, Hayashida CY, Bechara LR et al (2011) Pivotal role of Toll-like receptors 2 and 4, its adaptor molecule MyD88, and inflammasome complex in experimental tubule-interstitial nephritis. PLoS ONE 6:e29004PubMedPubMedCentralCrossRefGoogle Scholar
  30. Crean JK, Furlong F, Finlay D, Mitchell D, Murphy M et al (2004) Connective tissue growth factor [CTGF]/CCN2 stimulates mesangial cell migration through integrated dissolution of focal adhesion complexes and activation of cell polarization. FASEB J 18:1541–1543PubMedCrossRefGoogle Scholar
  31. D’Agati V, Schmidt AM (2010) RAGE and the pathogenesis of chronic kidney disease. Nat Rev Nephrol 6:352–360PubMedCrossRefGoogle Scholar
  32. Dai Y, Gu L, Yuan W, Yu Q, Ni Z et al (2013) Podocyte-specific deletion of signal transducer and activator of transcription 3 attenuates nephrotoxic serum-induced glomerulonephritis. Kidney Int 84:950–961PubMedPubMedCentralCrossRefGoogle Scholar
  33. Danelli L, Madjene LC, Madera-Salcedo I, Gautier G, Pacreau E et al (2017) Early phase mast cell activation determines the chronic outcome of renal ischemia-reperfusion injury. J Immunol 198:2374–2382PubMedCrossRefGoogle Scholar
  34. Daroux M, Prevost G, Maillard-Lefebvre H, Gaxatte C, D’Agati VD et al (2010) Advanced glycation end-products: implications for diabetic and non-diabetic nephropathies. Diabetes Metab 36:1–10PubMedCrossRefGoogle Scholar
  35. Das R, Xu S, Quan X, Nguyen TT, Kong ID et al (2014) Upregulation of mitochondrial Nox4 mediates TGF-beta-induced apoptosis in cultured mouse podocytes. Am J Physiol Renal Physiol 306:F155–F167PubMedCrossRefGoogle Scholar
  36. Das F, Ghosh-Choudhury N, Venkatesan B, Kasinath BS, Ghosh Choudhury G (2017) PDGF receptor-beta uses Akt/mTORC1 signaling node to promote high glucose-induced renal proximal tubular cell collagen I (alpha2) expression. Am J Physiol Renal Physiol 313:F291–F307PubMedPubMedCentralCrossRefGoogle Scholar
  37. Deelman L, Sharma K (2009) Mechanisms of kidney fibrosis and the role of antifibrotic therapies. Curr Opin Nephrol Hypertens 18:85–90PubMedCrossRefGoogle Scholar
  38. Demmers MW, Baan CC, van Beelen E, Ijzermans JN, Weimar W, Rowshani AT (2013) Differential effects of activated human renal epithelial cells on T-cell migration. PLoS ONE 8:e64916PubMedPubMedCentralCrossRefGoogle Scholar
  39. Disteldorf EM, Krebs CF, Paust HJ, Turner JE, Nouailles G et al (2015) CXCL5 drives neutrophil recruitment in TH17-mediated GN. J Am Soc Nephrol 26:55–66PubMedCrossRefGoogle Scholar
  40. Djudjaj S, Boor P (2018) Cellular and molecular mechanisms of kidney fibrosis. Mol Aspects MedGoogle Scholar
  41. Dong Y, Yang M, Zhang J, Peng X, Cheng J, Cui T, Du J (2016) Depletion of CD8+ T cells exacerbates CD4+ T cell-induced monocyte-to-fibroblast transition in renal fibrosis. J Immunol 196:1874–1881PubMedPubMedCentralCrossRefGoogle Scholar
  42. Duffield JS, Humphreys BD (2011) Origin of new cells in the adult kidney: results from genetic labeling techniques. Kidney Int 79:494–501PubMedCrossRefGoogle Scholar
  43. Durvasula RV, Shankland SJ (2006) The renin-angiotensin system in glomerular podocytes: mediator of glomerulosclerosis and link to hypertensive nephropathy. Curr Hypertens Rep 8:132–138PubMedCrossRefGoogle Scholar
  44. Durvasula RV, Shankland SJ (2008) Activation of a local renin angiotensin system in podocytes by glucose. Am J Physiol Renal Physiol 294:F830–F839PubMedCrossRefGoogle Scholar
  45. Eardley KS, Kubal C, Zehnder D, Quinkler M, Lepenies J et al (2008) The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease. Kidney Int 74:495–504PubMedCrossRefGoogle Scholar
  46. Eddy AA, Neilson EG (2006) Chronic kidney disease progression. J Am Soc Nephrol 17:2964–2966PubMedCrossRefGoogle Scholar
  47. Eitner F, Bucher E, van Roeyen C, Kunter U, Rong S et al (2008) PDGF-C is a proinflammatory cytokine that mediates renal interstitial fibrosis. J Am Soc Nephrol 19:281–289PubMedPubMedCentralCrossRefGoogle Scholar
  48. Eremina V, Cui S, Gerber H, Ferrara N, Haigh J et al (2006) Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol 17:724–735CrossRefGoogle Scholar
  49. Fan JM, Ng YY, Hill PA, Nikolic-Paterson DJ, Mu W et al (1999) Transforming growth factor-beta regulates tubular epithelial-myofibroblast transdifferentiation in vitro. Kidney Int 56:1455–1467PubMedCrossRefGoogle Scholar
  50. Fan JM, Huang XR, Ng YY, Nikolic-Paterson DJ, Mu W et al (2001) Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta1-dependent mechanism in vitro. Am J Kidney Dis 37:820–831PubMedCrossRefGoogle Scholar
  51. Fine LG, Norman JT (2008) Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int 74:867–872PubMedCrossRefGoogle Scholar
  52. Floege J, Burg M, Hugo C, Gordon KL, Van Goor H et al (1998) Endogenous fibroblast growth factor-2 mediates cytotoxicity in experimental mesangioproliferative glomerulonephritis. J Am Soc Nephrol 9:792–801PubMedGoogle Scholar
  53. Floege J, Eitner F, Alpers CE (2008) A new look at platelet-derived growth factor in renal disease. J Am Soc Nephrol 19:12–23PubMedCrossRefGoogle Scholar
  54. Fogo AB (2011) The targeted podocyte. J Clin Invest 121:2142–2145PubMedPubMedCentralCrossRefGoogle Scholar
  55. Fu S, Zhang N, Yopp AC, Chen D, Mao M et al (2004) TGF-beta induces Foxp3+ T-regulatory cells from CD4+ CD25-precursors. Am J Transplant 4:1614–1627PubMedCrossRefGoogle Scholar
  56. Fujiu K, Manabe I, Nagai R (2011) Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice. J Clin Invest 121:3425–3441PubMedPubMedCentralCrossRefGoogle Scholar
  57. Fukuda K, Yoshitomi K, Yanagida T, Tokumoto M, Hirakata H (2001) Quantification of TGF-beta1 mRNA along rat nephron in obstructive nephropathy. Am J Physiol Renal Physiol 281:F513–F521PubMedCrossRefGoogle Scholar
  58. Funaba M, Ikeda T, Murakami M, Ogawa K, Nishino Y et al (2006) Transcriptional regulation of mouse mast cell protease-7 by TGF-beta. Biochem Biophys Acta 1759:166–170PubMedGoogle Scholar
  59. Gentle ME, Shi S, Daehn I, Zhang T, Qi H et al (2013) Epithelial cell TGFbeta signaling induces acute tubular injury and interstitial inflammation. J Am Soc Nephrol 24:787–799PubMedPubMedCentralCrossRefGoogle Scholar
  60. Gewin LS (2018) Renal fibrosis: primacy of the proximal tubule. Matrix Biol 68–69:248–262PubMedPubMedCentralCrossRefGoogle Scholar
  61. Gewin L, Bulus N, Mernaugh G, Moeckel G, Harris RC et al (2010) TGF-beta receptor deletion in the renal collecting system exacerbates fibrosis. J Am Soc Nephrol 21:1334–1343PubMedPubMedCentralCrossRefGoogle Scholar
  62. Gewin L, Vadivelu S, Neelisetty S, Srichai MB, Paueksakon P et al (2012) Deleting the TGF-beta receptor attenuates acute proximal tubule injury. J Am Soc Nephrol 23:2001–2011PubMedPubMedCentralCrossRefGoogle Scholar
  63. Gewin L, Zent R, Pozzi A (2017) Progression of chronic kidney disease: too much cellular talk causes damage. Kidney Int 91:552–560CrossRefGoogle Scholar
  64. Godel M, Hartleben B, Herbach N, Liu S, Zschiedrich S et al (2011) Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest 121:2197–2209PubMedPubMedCentralCrossRefGoogle Scholar
  65. Gomez-Guerrero C, Hernandez-Vargas P, Lopez-Franco O, Ortiz-Munoz G, Egido J (2005) Mesangial cells and glomerular inflammation: from the pathogenesis to novel therapeutic approaches. Curr Drug Targets Inflamm Allergy 4:341–351PubMedCrossRefGoogle Scholar
  66. Gorelik L, Flavell RA (2002) Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2:46–53PubMedCrossRefGoogle Scholar
  67. Grahammer F, Schell C, Huber TB (2013) The podocyte slit diaphragm–from a thin grey line to a complex signalling hub. Nat Rev Nephrol 9:587–598PubMedCrossRefGoogle Scholar
  68. Grande MT, Perez-Barriocanal F, Lopez-Novoa JM (2010) Role of inflammation in tubulo-interstitial damage associated to obstructive nephropathy. J Inflamm (Lond) 7:19CrossRefGoogle Scholar
  69. Grande MT, Sanchez-Laorden B, Lopez-Blau C, De Frutos CA, Boutet A et al (2015) Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med 21:989–997PubMedCrossRefGoogle Scholar
  70. Gratchev A, Guillot P, Hakiy N, Politz O, Orfanos CE, Schledzewski K, Goerdt S (2001) Alternatively activated macrophages differentially express fibronectin and its splice variants and the extracellular matrix protein betaIG-H3. Scand J Immunol 53:386–392PubMedCrossRefGoogle Scholar
  71. Gruber BL, Marchese MJ, Kew RR (1994) Transforming growth factor-beta 1 mediates mast cell chemotaxis. J Immunol 152:5860–5867PubMedGoogle Scholar
  72. Gruden G, Perin PC, Camussi G (2005) Insight on the pathogenesis of diabetic nephropathy from the study of podocyte and mesangial cell biology. Curr Diab Rev 1:27–40CrossRefGoogle Scholar
  73. Guerrot D, Dussaule JC, Kavvadas P, Boffa JJ, Chadjichristos CE, Chatziantoniou C (2012) Progression of renal fibrosis: the underestimated role of endothelial alterations. Fibrogenesis Tissue repair 5(Suppl 1):S15PubMedPubMedCentralCrossRefGoogle Scholar
  74. Guo S, Wietecha TA, Hudkins KL, Kida Y, Spencer MW et al (2011) Macrophages are essential contributors to kidney injury in murine cryoglobulinemic membranoproliferative glomerulonephritis. Kidney Int 80:946–958PubMedCrossRefGoogle Scholar
  75. Han Y, Ma FY, Tesch GH, Manthey CL, Nikolic-Paterson DJ (2011) c-fms blockade reverses glomerular macrophage infiltration and halts development of crescentic anti-GBM glomerulonephritis in the rat. Lab Invest 91:978–991PubMedCrossRefGoogle Scholar
  76. Han Y, Ma FY, Tesch GH, Manthey CL, Nikolic-Paterson DJ (2013) Role of macrophages in the fibrotic phase of rat crescentic glomerulonephritis. Am J Physiol Renal Physiol 304:F1043–F1053PubMedCrossRefGoogle Scholar
  77. Harris RC, Neilson EG (2006) Toward a unified theory of renal progression. Annu Rev Med 57:365–380CrossRefPubMedPubMedCentralGoogle Scholar
  78. Hathaway CK, Gasim AM, Grant R, Chang AS, Kim HS et al (2015) Low TGFbeta1 expression prevents and high expression exacerbates diabetic nephropathy in mice. Proc Natl Acad Sci USA 112:5815–5820PubMedCrossRefGoogle Scholar
  79. Hato T, El-Achkar TM, Dagher PC (2013) Sisters in arms: myeloid and tubular epithelial cells shape renal innate immunity. Am J Physiol Renal Physiol 304:F1243–F1251PubMedPubMedCentralCrossRefGoogle Scholar
  80. He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y (2009) Wnt/beta-catenin signaling promotes renal interstitial fibrosis. J Am Soc Nephrol 20:765–776PubMedPubMedCentralCrossRefGoogle Scholar
  81. Henderson NC, Mackinnon AC, Farnworth SL, Kipari T, Haslett C et al (2008) Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am J Pathol 172:288–298PubMedPubMedCentralCrossRefGoogle Scholar
  82. Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y et al (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117:3810–3820PubMedPubMedCentralGoogle Scholar
  83. Higgins DF, Kimura K, Iwano M, Haase VH (2008) Hypoxia-inducible factor signaling in the development of tissue fibrosis. Cell Cycle 7:1128–1132PubMedPubMedCentralCrossRefGoogle Scholar
  84. Hochane M, Raison D, Coquard C, Beraud C, Bethry A et al (2018) Parathyroid hormone-related protein modulates inflammation in mouse mesangial cells and blunts apoptosis by enhancing COX-2 expression. Am J Physiol Cell Physiol 314:C242–C253PubMedCrossRefGoogle Scholar
  85. Holdsworth SR, Summers SA (2008) Role of mast cells in progressive renal diseases. J Am Soc Nephrol 19:2254–2261PubMedCrossRefGoogle Scholar
  86. Huang XR, Chung AC, Wang XJ, Lai KN, Lan HY (2008a) Mice overexpressing latent TGF-beta1 are protected against renal fibrosis in obstructive kidney disease. Am J Physiol Renal Physiol 295:F118–F127PubMedPubMedCentralCrossRefGoogle Scholar
  87. Huang XR, Chung AC, Zhou L, Wang XJ, Lan HY (2008b) Latent TGF-beta1 protects against crescentic glomerulonephritis. J Am Soc Nephrol 19:233–242PubMedPubMedCentralCrossRefGoogle Scholar
  88. Humphreys BD (2018) Mechanisms of renal fibrosis. Annu Rev Physiol 80:309–326PubMedCrossRefGoogle Scholar
  89. Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT et al (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176:85–97PubMedPubMedCentralCrossRefGoogle Scholar
  90. Inoki K, Mori H, Wang J, Suzuki T, Hong S et al (2011) mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest 121:2181–2196PubMedPubMedCentralCrossRefGoogle Scholar
  91. Kanasaki K, Taduri G, Koya D (2013) Diabetic nephropathy: the role of inflammation in fibroblast activation and kidney fibrosis. Front Endocrinol 4:7CrossRefGoogle Scholar
  92. Kang DH, Kanellis J, Hugo C, Truong L, Anderson S et al (2002) Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 13:806–816PubMedCrossRefGoogle Scholar
  93. Kato N, Yuzawa Y, Kosugi T, Hobo A, Sato W et al (2009) The E-selectin ligand basigin/CD147 is responsible for neutrophil recruitment in renal ischemia/reperfusion. J Am Soc Nephrol 20:1565–1576PubMedPubMedCentralCrossRefGoogle Scholar
  94. Kelly KJ, Williams WW Jr, Colvin RB, Bonventre JV (1994) Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc Nati Acad Sci USA 91:812–816CrossRefGoogle Scholar
  95. Kelly KJ, Williams WW Jr, Colvin RB, Meehan SM, Springer TA et al (1996) Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest 97:1056–1063PubMedPubMedCentralCrossRefGoogle Scholar
  96. Kelly KJ, Burford JL, Dominguez JH (2009) Postischemic inflammatory syndrome: a critical mechanism of progression in diabetic nephropathy. Am J Physiol Renal Physiol 297:F923–F931PubMedCrossRefGoogle Scholar
  97. Kim DH, Moon SO, Jung YJ, Lee AS, Kang KP et al (2009) Mast cells decrease renal fibrosis in unilateral ureteral obstruction. Kidney Int 75:1031–1038PubMedPubMedCentralCrossRefGoogle Scholar
  98. Kim SM, Lee SH, Lee A, Kim DJ, Kim YG et al (2015) Targeting T helper 17 by mycophenolate mofetil attenuates diabetic nephropathy progression. Transl Res 166:375–383PubMedCrossRefGoogle Scholar
  99. Kimura K, Iwano M, Higgins DF, Yamaguchi Y, Nakatani K et al (2008) Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Renal Physiol 295:F1023–F1029PubMedPubMedCentralCrossRefGoogle Scholar
  100. Kitamoto K, Machida Y, Uchida J, Izumi Y, Shiota M et al (2009) Effects of liposome clodronate on renal leukocyte populations and renal fibrosis in murine obstructive nephropathy. J Pharmacol Sci 111:285–292PubMedCrossRefGoogle Scholar
  101. Kitamura M, Suto TS (1997) TGF-beta and glomerulonephritis: anti-inflammatory versus prosclerotic actions. Nephrol Dial Transplant 12:669–679PubMedCrossRefGoogle Scholar
  102. Kitching AR, Holdsworth SR (2011) The emergence of TH17 cells as effectors of renal injury. J Am Soc Nephrol 22:235–238PubMedCrossRefGoogle Scholar
  103. Ko GJ, Boo CS, Jo SK, Cho WY, Kim HK (2008) Macrophages contribute to the development of renal fibrosis following ischaemia/reperfusion-induced acute kidney injury. Nephrol Dial Transplant 23:842–852PubMedCrossRefGoogle Scholar
  104. Kondo S, Kagami S, Kido H, Strutz F, Muller GA, Kuroda Y (2001) Role of mast cell tryptase in renal interstitial fibrosis. J Am Soc Nephrol 12:1668–1676PubMedGoogle Scholar
  105. Kong D, Li Y, Wang Z, Banerjee S, Ahmad A et al (2009) miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells 27:1712–1721PubMedPubMedCentralCrossRefGoogle Scholar
  106. Ku CH, White KE, Dei Cas A, Hayward A, Webster Z et al (2008) Inducible overexpression of sFlt-1 in podocytes ameliorates glomerulopathy in diabetic mice. Diabetes 57:2824–2833PubMedPubMedCentralCrossRefGoogle Scholar
  107. Lai KN, Leung JC, Chan LY, Saleem MA, Mathieson PW et al (2008) Activation of podocytes by mesangial-derived TNF-alpha: glomerulo-podocytic communication in IgA nephropathy. Am J Physiol Renal Physiol 294:F945–F955PubMedCrossRefGoogle Scholar
  108. Lai KN, Leung JC, Chan LY, Saleem MA, Mathieson PW et al (2009) Podocyte injury induced by mesangial-derived cytokines in IgA nephropathy. Nephrol Dial Transplant 24:62–72PubMedCrossRefGoogle Scholar
  109. Lan HY (2011) Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation. Int J Biol Sci 7:1056–1067PubMedPubMedCentralCrossRefGoogle Scholar
  110. Lan HY, Nikolic-Paterson DJ, Mu W, Atkins RC (1995) Local macrophage proliferation in the progression of glomerular and tubulointerstitial injury in rat anti-GBM glomerulonephritis. Kidney Int 48:753–760PubMedCrossRefGoogle Scholar
  111. Lan HY, Bacher M, Yang N, Mu W, Nikolic-Paterson DJ et al (1997) The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J Exp Med 185:1455–1465PubMedPubMedCentralCrossRefGoogle Scholar
  112. Laping NJ, Olson BA, Ho T, Ziyadeh FN, Albrightson CR (2000) Hepatocyte growth factor: a regulator of extracellular matrix genes in mouse mesangial cells. Biochem Pharmacol 59:847–853PubMedCrossRefGoogle Scholar
  113. LeBleu VS, Kalluri R (2011) Blockade of PDGF receptor signaling reduces myofibroblast number and attenuates renal fibrosis. Kidney Int 80:1119–1121PubMedPubMedCentralCrossRefGoogle Scholar
  114. LeBleu VS, Taduri G, O’Connell J, Teng Y, Cooke VG et al (2013) Origin and function of myofibroblasts in kidney fibrosis. Nat Med 19:1047–1053PubMedPubMedCentralCrossRefGoogle Scholar
  115. Lebrin F, Deckers M, Bertolino P, Ten Dijke P (2005) TGF-beta receptor function in the endothelium. Cardiovascular Res 65:599–608CrossRefGoogle Scholar
  116. Lee SB, Kalluri R (2010) Mechanistic connection between inflammation and fibrosis. Kidney Int Suppl S22–S26CrossRefGoogle Scholar
  117. 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
  118. Li Y, Kang YS, Dai C, Kiss LP, Wen X, Liu Y (2008) Epithelial-to-mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria. Am J Pathol 172:299–308PubMedPubMedCentralCrossRefGoogle Scholar
  119. Li J, Qu X, Yao J, Caruana G, Ricardo SD et al (2010) Blockade of endothelial-mesenchymal transition by a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. Diabetes 59:2612–2624PubMedPubMedCentralCrossRefGoogle Scholar
  120. Lin M, Tang SC (2013) Toll-like receptors: sensing and reacting to diabetic injury in the kidney. Nephrol Dial TransplantGoogle Scholar
  121. Lin SL, Kisseleva T, Brenner DA, Duffield JS (2008) Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 173:1617–1627PubMedPubMedCentralCrossRefGoogle Scholar
  122. Lin SL, Castano AP, Nowlin BT, Lupher ML Jr, Duffield JS (2009) Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol 183:6733–6743CrossRefGoogle Scholar
  123. Lin M, Yiu WH, Wu HJ, Chan LY, Leung JC et al (2012) Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. J Am Soc Nephrol 23:86–102PubMedCrossRefGoogle Scholar
  124. Lin JR, Zheng YJ, Zhang ZB, Shen WL, Li XD et al (2018) Suppression of endothelial-to-mesenchymal transition by SIRT (Sirtuin) 3 alleviated the development of hypertensive renal injury. HypertensionGoogle Scholar
  125. Liu Y (2004) Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention. J Am Soc Nephrol 15:1–12CrossRefGoogle Scholar
  126. Liu Y (2006) Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 69:213–217CrossRefGoogle Scholar
  127. Liu Y (2010) New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 21:212–222PubMedPubMedCentralCrossRefGoogle Scholar
  128. Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 7:684–696PubMedPubMedCentralCrossRefGoogle Scholar
  129. Liu F, Chen HY, Huang XR, Chung AC, Zhou L et al (2011) C-reactive protein promotes diabetic kidney disease in a mouse model of type 1 diabetes. Diabetologia 54:2713–2723PubMedCrossRefGoogle Scholar
  130. Liu L, Kou P, Zeng Q, Pei G, Li Y et al (2012) CD4+ T Lymphocytes, especially Th2 cells, contribute to the progress of renal fibrosis. Am J Nephrol 36:386–396PubMedCrossRefGoogle Scholar
  131. Liu P, Lassen E, Nair V, Berthier CC, Suguro M et al (2017) Transcriptomic and proteomic profiling provides insight into mesangial cell function in IgA nephropathy. J Am Soc Nephrol 28:2961–2972PubMedPubMedCentralCrossRefGoogle Scholar
  132. 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
  133. Loeffler I, Wolf G (2013) Transforming growth factor-beta and the progression of renal disease. Nephrol Dial TransplantGoogle Scholar
  134. Lopez-Hernandez FJ, Lopez-Novoa JM (2012) Role of TGF-beta in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Res 347:141–154PubMedPubMedCentralCrossRefGoogle Scholar
  135. Lovisa S, LeBleu VS, Tampe B, Sugimoto H, Vadnagara K et al (2015) Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med 21:998–1009PubMedPubMedCentralCrossRefGoogle Scholar
  136. Lu J, Cao Q, Zheng D, Sun Y, Wang C et al (2013) Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease. Kidney Int 84:745–755PubMedCrossRefGoogle Scholar
  137. Lu Y, Mei Y, Chen L, Wu L, Wang X et al (2018) The role of transcriptional factor D-site-binding protein in circadian CCL2 gene expression in anti-Thy1 nephritis. Cell Mol ImmunolGoogle Scholar
  138. Lv W, Booz GW, Wang Y, Fan F, Roman RJ (2018) Inflammation and renal fibrosis: recent developments on key signaling molecules as potential therapeutic targets. Eur J Pharmacol 820:65–76PubMedCrossRefPubMedCentralGoogle Scholar
  139. Lyons RM, Gentry LE, Purchio AF, Moses HL (1990) Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol 110:1361–1367PubMedCrossRefGoogle Scholar
  140. Ma LJ, Yang H, Gaspert A, Carlesso G, Barty MM et al (2003) Transforming growth factor-beta-dependent and -independent pathways of induction of tubulointerstitial fibrosis in beta6(−/−) mice. Am J Pathol 163:1261–1273PubMedPubMedCentralCrossRefGoogle Scholar
  141. Ma FY, Flanc RS, Tesch GH, Bennett BL, Friedman GC et al (2009a) Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat. Lab Inves 89:470–484CrossRefGoogle Scholar
  142. Ma FY, Liu J, Kitching AR, Manthey CL, Nikolic-Paterson DJ (2009b) Targeting renal macrophage accumulation via c-fms kinase reduces tubular apoptosis but fails to modify progressive fibrosis in the obstructed rat kidney. Am J Physiol Renal Physiol 296:F177–F185PubMedCrossRefGoogle Scholar
  143. Ma FY, Ikezumi Y, Nikolic-Paterson DJ (2010) Macrophage signaling pathways: a novel target in renal disease. Semin Nephrol 30:334–344PubMedCrossRefGoogle Scholar
  144. Mack M, Rosenkranz AR (2009) Basophils and mast cells in renal injury. Kidney Int 76:1142–1147PubMedPubMedCentralCrossRefGoogle Scholar
  145. Margulis A, Nocka KH, Brennan AM, Deng B, Fleming M et al (2009) Mast cell-dependent contraction of human airway smooth muscle cell-containing collagen gels: influence of cytokines, matrix metalloproteases, and serine proteases. J Immunol 183:1739–1750PubMedCrossRefGoogle Scholar
  146. Mathieson PW (2009) Update on the podocyte. Curr Opin Nephrol Hypertens 18:206–211PubMedCrossRefGoogle Scholar
  147. Mehrotra P, Patel JB, Ivancic CM, Collett JA, Basile DP (2015) Th-17 cell activation in response to high salt following acute kidney injury is associated with progressive fibrosis and attenuated by AT-1R antagonism. Kidney Int 88:776–784PubMedPubMedCentralCrossRefGoogle Scholar
  148. Meldrum KK, Zhang H, Hile KL, Moldower LL, Dong Z, Meldrum DR (2012) Profibrotic effect of interleukin-18 in HK-2 cells is dependent on stimulation of the Toll-like receptor 4 (TLR4) promoter and increased TLR4 expression. J Biol Chem 287:40391–40399PubMedPubMedCentralCrossRefGoogle Scholar
  149. Meng XM, Huang XR, Chung AC, Qin W, Shao X et al (2010) Smad2 protects against TGF-beta/Smad3-mediated renal fibrosis. J Am Soc Nephrol 21:1477–1487PubMedPubMedCentralCrossRefGoogle Scholar
  150. Meng XM, Huang XR, Xiao J, Chen HY, Zhong X, Chung AC, Lan HY (2012a) Diverse roles of TGF-beta receptor II in renal fibrosis and inflammation in vivo and in vitro. J Pathol 227:175–188PubMedCrossRefGoogle Scholar
  151. Meng XM, Huang XR, Xiao J, Chung AC, Qin W et al (2012b) Disruption of Smad4 impairs TGF-beta/Smad3 and Smad7 transcriptional regulation during renal inflammation and fibrosis in vivo and in vitro. Kidney Int 81:266–279PubMedCrossRefGoogle Scholar
  152. Meng XM, Chung AC, Lan HY (2013) Role of the TGF-beta/BMP-7/Smad pathways in renal diseases. Clin Sci (Lond) 124:243–254CrossRefGoogle Scholar
  153. Meng XM, Nikolic-Paterson DJ, Lan HY (2014) Inflammatory processes in renal fibrosis. Nat Rev Nephrol 10:493–503PubMedCrossRefGoogle Scholar
  154. Meng XM, Tang PM, Li J, Lan HY (2015) TGF-beta/Smad signaling in renal fibrosis. Front Physiol 6:82PubMedPubMedCentralCrossRefGoogle Scholar
  155. Meng XM, Nikolic-Paterson DJ, Lan HY (2016a) TGF-beta: the master regulator of fibrosis. Nat Rev Nephrol 12:325–338CrossRefGoogle Scholar
  156. Meng XM, Wang S, Huang XR, Yang C, Xiao J et al (2016b) Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis. Cell Death Dis 7:e2495PubMedPubMedCentralCrossRefGoogle Scholar
  157. Mezzano SA, Ruiz-Ortega M, Egido J (2001) Angiotensin II and renal fibrosis. Hypertension 38:635–638PubMedCrossRefGoogle Scholar
  158. Miyazawa S, Hotta O, Doi N, Natori Y, Nishikawa K (2004) Role of mast cells in the development of renal fibrosis: use of mast cell-deficient rats. Kidney Int 65: 2228–2237PubMedCrossRefGoogle Scholar
  159. Mohamed R, Jayakumar C, Chen F, Fulton D, Stepp D et al (2016) Low-dose IL-17 therapy prevents and reverses diabetic nephropathy, metabolic syndrome, and associated organ fibrosis. J Am Soc Nephrol 27:745–765PubMedCrossRefGoogle Scholar
  160. Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL et al (1999) The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96:319–328PubMedCrossRefGoogle Scholar
  161. Nakagawa T, Lan HY, Zhu HJ, Kang DH, Schreiner GF, Johnson RJ (2004a) Differential regulation of VEGF by TGF-beta and hypoxia in rat proximal tubular cells. Am J Physiol Renal Physiol 287:F658–F664PubMedCrossRefGoogle Scholar
  162. Nakagawa T, Li JH, Garcia G, Mu W, Piek E et al (2004b) TGF-beta induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathways. Kidney Int 66:605–613PubMedCrossRefGoogle Scholar
  163. Negre-Salvayre A, Coatrieux C, Ingueneau C, Salvayre R (2008) Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Br J Pharmacol 153:6–20PubMedCrossRefGoogle Scholar
  164. Nguan CY, Du C (2009) Renal tubular epithelial cells as immunoregulatory cells in renal allograft rejection. Transplant Rev (Orlando) 23:129–138CrossRefGoogle Scholar
  165. Niedermeier M, Reich B, Rodriguez Gomez M, Denzel A, Schmidbauer K et al (2009) CD4 +T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc Nati Acad Sci USA 106:17892–17897CrossRefGoogle Scholar
  166. Nielsen R, Mollet G, Esquivel EL, Weyer K, Nielsen PK et al (2013) Increased lysosomal proteolysis counteracts protein accumulation in the proximal tubule during focal segmental glomerulosclerosis. Kidney Int 84:902–910PubMedCrossRefGoogle Scholar
  167. Niranjan T, Bielesz B, Gruenwald A, Ponda MP, Kopp JB et al (2008) The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med 14:290–298PubMedCrossRefGoogle Scholar
  168. Nishida M, Hamaoka K (2008) Macrophage phenotype and renal fibrosis in obstructive nephropathy. Nephron Exp Nephrol 110:e31–e36PubMedCrossRefGoogle Scholar
  169. Ostendorf T, Rong S, Boor P, Wiedemann S, Kunter U et al (2006) Antagonism of PDGF-D by human antibody CR170 prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 17:1054–1062PubMedCrossRefGoogle Scholar
  170. Ostendorf T, Eitner F, Floege J (2012) The PDGF family in renal fibrosis. Pediatr Nephrol 27:1041–1050PubMedCrossRefGoogle Scholar
  171. Paust HJ, Turner JE, Steinmetz OM, Peters A, Heymann F et al (2009) The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis. J Am Soc Nephrol 2:969–979CrossRefGoogle Scholar
  172. Peng X, Xiao Z, Zhang J, Li Y, Dong Y, Du J (2015) IL-17A produced by both gammadelta T and Th17 cells promotes renal fibrosis via RANTES-mediated leukocyte infiltration after renal obstruction. J Pathol 235:79–89PubMedCrossRefGoogle Scholar
  173. Pober JS, Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7:803–815PubMedCrossRefGoogle Scholar
  174. Pons M, Ali L, Beghdadi W, Danelli L, Alison M et al (2017) Mast cells and MCPT4 chymase promote renal impairment after partial ureteral obstruction. Front Immunol 8:450PubMedPubMedCentralCrossRefGoogle Scholar
  175. Pulskens WP, Rampanelli E, Teske GJ, Butter LM, Claessen N et al (2010) TLR4 promotes fibrosis but attenuates tubular damage in progressive renal injury. J Am Soc Nephrol 21:1299–1308PubMedPubMedCentralCrossRefGoogle Scholar
  176. Qiao X, Rao P, Zhang Y, Liu L, Pang M et al (2018) Redirecting TGF-beta signaling through the beta-catenin/Foxo complex prevents kidney fibrosis. J Am Soc Nephrol 29:557–570PubMedCrossRefGoogle Scholar
  177. Reich B, Schmidbauer K, Rodriguez Gomez M, Johannes Hermann F, Gobel N et al (2013) Fibrocytes develop outside the kidney but contribute to renal fibrosis in a mouse model. Kidney Int 84:78–89PubMedPubMedCentralCrossRefGoogle Scholar
  178. Reilkoff RA, Bucala R, Herzog EL (2011) Fibrocytes: emerging effector cells in chronic inflammation. Nat Rev Immunol 11:427–435PubMedPubMedCentralCrossRefGoogle Scholar
  179. Ricardo SD, van Goor H, Eddy AA (2008) Macrophage diversity in renal injury and repair. J Clin Invest 118:3522–3530PubMedPubMedCentralCrossRefGoogle Scholar
  180. Robertson H, Ali S, McDonnell BJ, Burt AD, Kirby JA (2004) Chronic renal allograft dysfunction: the role of T cell-mediated tubular epithelial to mesenchymal cell transition. J Am Soc Nephrol 15:390–397PubMedCrossRefGoogle Scholar
  181. Rutkowski JM, Wang ZV, Park AS, Zhang J, Zhang D et al (2013) Adiponectin promotes functional recovery after podocyte ablation. J Am Soc Nephrol 24:268–282PubMedPubMedCentralCrossRefGoogle Scholar
  182. Sakai N, Wada T, Yokoyama H, Lipp M, Ueha S, Matsushima K, Kaneko S (2006) Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR182 signaling regulates fibrocytes in renal fibrosis. Proc Nati Acad Sci USA 103:14098–14103CrossRefGoogle Scholar
  183. Sam R, Wanna L, Gudehithlu KP, Garber SL, Dunea G et al (2006) Glomerular epithelial cells transform to myofibroblasts: early but not late removal of TGF-beta1 reverses transformation. Transl Res 148:142–148PubMedCrossRefGoogle Scholar
  184. Scandiuzzi L, Beghdadi W, Daugas E, Abrink M, Tiwari N et al (2010) Mouse mast cell protease-4 deteriorates renal function by contributing to inflammation and fibrosis in immune complex-mediated glomerulonephritis. J Immunol 185:624–633PubMedPubMedCentralCrossRefGoogle Scholar
  185. Schiffer M, Bitzer M, Roberts IS, Kopp JB, ten Dijke P et al (2001) Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest 108:807–816PubMedPubMedCentralCrossRefGoogle Scholar
  186. Schlondorff D, Banas B (2009) The mesangial cell revisited: no cell is an island. J Am Soc Nephrol 20:1179–1187PubMedCrossRefGoogle Scholar
  187. Schnaper HW, Hayashida T, Hubchak SC, Poncelet AC (2003) TGF-beta signal transduction and mesangial cell fibrogenesis. Am J Physiol Renal Physiol 284:F243–F252CrossRefGoogle Scholar
  188. Schnoor M, Cullen P, Lorkowski J, Stolle K, Robenek H et al (2008) Production of type VI collagen by human macrophages: a new dimension in macrophage functional heterogeneity. J Immunol 180:5707–5719PubMedCrossRefGoogle Scholar
  189. Schwartzman M, Reginensi A, Wong JS, Basgen JM, Meliambro K et al (2016) Podocyte-specific deletion of yes-associated protein causes FSGS and progressive renal failure. J Am Soc Nephrol 27:216–226PubMedCrossRefGoogle Scholar
  190. Shanmugam N, Figarola JL, Li Y, Swiderski PM, Rahbar S, Natarajan R (2008) Proinflammatory effects of advanced lipoxidation end products in monocytes. Diabetes 57:879–888PubMedCrossRefGoogle Scholar
  191. Shao DD, Suresh R, Vakil V, Gomer RH, Pilling D (2008) Pivotal Advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol 83:1323–1333PubMedPubMedCentralCrossRefGoogle Scholar
  192. Sharma S, Sirin Y, Susztak K (2011) The story of Notch and chronic kidney disease. Curr Opin Nephrol Hypertens 20:56–61PubMedPubMedCentralCrossRefGoogle Scholar
  193. Shi XY, Hou FF, Niu HX, Wang GB, Xie D (2008) Advanced oxidation protein products promote inflammation in diabetic kidney through activation of renal nicotinamide adenine dinucleotide phosphate oxidase. Endocrinology 149:1829–1839PubMedCrossRefGoogle Scholar
  194. Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O et al (1999) Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286:312–315PubMedCrossRefGoogle Scholar
  195. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795PubMedPubMedCentralCrossRefGoogle Scholar
  196. Siddiqi FS, Advani A (2013) Endothelial-podocyte crosstalk: the missing link between endothelial dysfunction and albuminuria in diabetes. Diabetes 62:3647–3655PubMedPubMedCentralCrossRefGoogle Scholar
  197. Strutz F, Zeisberg M (2006) Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol 17:2992–2998PubMedPubMedCentralCrossRefGoogle Scholar
  198. Summers SA, Gan PY, Dewage L, Ma FT, Ooi JD et al (2012) Mast cell activation and degranulation promotes renal fibrosis in experimental unilateral ureteric obstruction. Kidney Int 82:676–685PubMedCrossRefGoogle Scholar
  199. Tang WW, Ulich TR, Lacey DL, Hill DC, Qi M et al (1996) Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. Am J Pathol 148:1169–1180PubMedPubMedCentralGoogle Scholar
  200. Taniguchi K, Xia L, Goldberg HJ, Lee KW, Shah A et al (2013) Inhibition of Src kinase blocks high glucose-induced EGFR transactivation and collagen synthesis in mesangial cells and prevents diabetic nephropathy in mice. Diabetes 62:3874–3886PubMedPubMedCentralCrossRefGoogle Scholar
  201. Tapmeier TT, Fearn A, Brown K, Chowdhury P, Sacks SH et al (2010) Pivotal role of CD4+ T cells in renal fibrosis following ureteric obstruction. Kidney Int 78:351–362PubMedPubMedCentralCrossRefGoogle Scholar
  202. Tipping PG, Holdsworth SR (2006) T cells in crescentic glomerulonephritis. J Am Soc Nephrol 17:1253–1263PubMedCrossRefGoogle Scholar
  203. Turner JE, Paust HJ, Steinmetz OM, Panzer U (2010) The Th17 immune response in renal inflammation. Kidney Int 77:1070–1075PubMedCrossRefGoogle Scholar
  204. Ueno T, Kobayashi N, Nakayama M, Takashima Y, Ohse T et al (2013) Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss. Kidney Int 83:1065–1075PubMedCrossRefGoogle Scholar
  205. van Roeyen CR, Eitner F, Boor P, Moeller MJ, Raffetseder U et al (2011) Induction of progressive glomerulonephritis by podocyte-specific overexpression of platelet-derived growth factor-D. Kidney Int 80:1292–1305PubMedCrossRefGoogle Scholar
  206. Venkatachalam MA, Griffin KA, Lan R, Geng H, Saikumar P, Bidani AK (2010) Acute kidney injury: a springboard for progression in chronic kidney disease. Am J Physiol Renal Physiol 298:F1078–F1094PubMedPubMedCentralCrossRefGoogle Scholar
  207. Vernon MA, Mylonas KJ, Hughes J (2010) Macrophages and renal fibrosis. Semin Nephrol 30:302–317PubMedPubMedCentralCrossRefGoogle Scholar
  208. Veron D, Reidy KJ, Bertuccio C, Teichman J, Villegas G et al (2010) Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int 77:989–999PubMedCrossRefGoogle Scholar
  209. Veron D, Bertuccio CA, Marlier A, Reidy K, Garcia AM et al (2011) Podocyte vascular endothelial growth factor (Vegf(1)(6)(4)) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. Diabetologia 54:1227–1241PubMedPubMedCentralCrossRefGoogle Scholar
  210. Wada T, Sakai N, Matsushima K, Kaneko S (2007) Fibrocytes: a new insight into kidney fibrosis. Kidney Int 72:269–273PubMedCrossRefGoogle Scholar
  211. Wang YM, Zhang GY, Wang Y, Hu M, Wu H et al (2006) Foxp3-transduced polyclonal regulatory T cells protect against chronic renal injury from adriamycin. J Am Soc Nephrol 17:697–706PubMedCrossRefGoogle Scholar
  212. Wang Y, Wang YP, Zheng G, Lee VW, Ouyang L et al (2007) Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int 72:290–299PubMedCrossRefGoogle Scholar
  213. Wang Y, Deb DK, Zhang Z, Sun T, Liu W et al (2012) Vitamin D receptor signaling in podocytes protects against diabetic nephropathy. J Am Soc Nephrol 23:1977–1986PubMedPubMedCentralCrossRefGoogle Scholar
  214. Wang H, Wang J, Bai Y, Li J, Li L, Dong Y (2016a) CD11c(+) CD8(+) T Cells Reduce Renal Fibrosis Following Ureteric Obstruction by Inducing Fibroblast Apoptosis. Int J Mol Sci 18PubMedCentralCrossRefPubMedGoogle Scholar
  215. Wang S, Meng XM, Ng YY, Ma FY, Zhou S et al (2016b) TGF-beta/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis. Oncotarget 7:8809–8822PubMedPubMedCentralGoogle Scholar
  216. Wang X, Yao B, Wang Y, Fan X, Wang S et al (2017a) Macrophage cyclooxygenase-2 protects against development of diabetic nephropathy. Diabetes 66:494–504PubMedCrossRefGoogle Scholar
  217. Wang YY, Jiang H, Pan J, Huang XR, Wang YC et al (2017b) Macrophage-to- myofibroblast transition contributes to interstitial fibrosis in chronic renal allograft injury. J Am Soc Nephrol 28:2053–2067PubMedPubMedCentralCrossRefGoogle Scholar
  218. Wasse H, Naqvi N, Husain A (2012) Impact of mast cell chymase on renal disease progression. Curr Hypertens Rev 8:15–23PubMedPubMedCentralCrossRefGoogle Scholar
  219. Wilkinson L, Gilbert T, Sipos A, Toma I, Pennisi DJ et al (2009) Loss of renal microvascular integrity in postnatal Crim1 hypomorphic transgenic mice. Kidney Int 76:1161–1171PubMedCrossRefGoogle Scholar
  220. Wynes MW, Frankel SK, Riches DW (2004) IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal. J Leukoc Biol 76:1019–1027PubMedCrossRefGoogle Scholar
  221. Xavier S, Vasko R, Matsumoto K, Zullo JA, Chen R et al (2015) Curtailing endothelial TGF-beta signaling is sufficient to reduce endothelial-mesenchymal transition and fibrosis in CKD. J Am Soc Nephrol 26:817–829PubMedCrossRefPubMedCentralGoogle Scholar
  222. Yamaguchi Y, Iwano M, Suzuki D, Nakatani K, Kimura K et al (2009) Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy. Am J Kidney Dis 54:653–664PubMedCrossRefGoogle Scholar
  223. Yang N, Isbel NM, Nikolic-Paterson DJ, Li Y, Ye R et al (1998a) Local macrophage proliferation in human glomerulonephritis. Kidney Int 54:143–151PubMedCrossRefGoogle Scholar
  224. Yang N, Wu LL, Nikolic-Paterson DJ, Ng YY, Yang WC et al (1998b) Local macrophage and myofibroblast proliferation in progressive renal injury in the rat remnant kidney. Nephrol Dial Transplant 13:1967–1974PubMedCrossRefGoogle Scholar
  225. Yang J, Dai C, Liu Y (2002) Hepatocyte growth factor gene therapy and angiotensin II blockade synergistically attenuate renal interstitial fibrosis in mice. J Am Soc Nephrol 13:2464–2477PubMedCrossRefGoogle Scholar
  226. Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV (2010) Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 16:535–543, 531p following 143PubMedPubMedCentralCrossRefGoogle Scholar
  227. Yokoi H, Mukoyama M, Mori K, Kasahara M, Suganami T et al (2008) Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice. Kidney Int 73:446–455PubMedCrossRefGoogle Scholar
  228. You H, Gao T, Cooper TK, Brian Reeves W, Awad AS (2013) Macrophages directly mediate diabetic renal injury. Am J Physiol Renal Physiol 305:F1719–F1727PubMedPubMedCentralCrossRefGoogle Scholar
  229. You H, Gao T, Raup-Konsavage WM, Cooper TK, Bronson SK et al (2017) Podocyte-specific chemokine (C-C motif) receptor 2 overexpression mediates diabetic renal injury in mice. Kidney Int 91:671–682PubMedCrossRefGoogle Scholar
  230. Zeisberg M, Neilson EG (2010) Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol 21:1819–1834PubMedPubMedCentralCrossRefGoogle Scholar
  231. Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R (2008) Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol 19:2282–2287PubMedPubMedCentralCrossRefGoogle Scholar
  232. Zeng F, Kloepfer LA, Finney C, Diedrich A, Harris RC (2016) Specific endothelial heparin-binding EGF-like growth factor deletion ameliorates renal injury induced by chronic angiotensin II infusion. Am J Physiol Renal Physiol 311:F695–F707PubMedPubMedCentralCrossRefGoogle Scholar
  233. Zhang B, Ramesh G, Uematsu S, Akira S, Reeves WB (2008) TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. J Am Soc Nephrol 19:923–932PubMedPubMedCentralCrossRefGoogle Scholar
  234. Zhang F, Tsai S, Kato K, Yamanouchi D, Wang C et al (2009) Transforming growth factor-beta promotes recruitment of bone marrow cells and bone marrow-derived mesenchymal stem cells through stimulation of MCP-1 production in vascular smooth muscle cells. J Biol Chem 284:17564–17574PubMedPubMedCentralCrossRefGoogle Scholar
  235. Zheng G, Wang Y, Mahajan D, Qin X, Alexander SI, Harris DC (2005) The role of tubulointerstitial inflammation. Kidney Int Suppl S96–S100CrossRefGoogle Scholar
  236. Zhou LL, Hou FF, Wang GB, Yang F, Xie D, Wang YP, Tian JW (2009) Accumulation of advanced oxidation protein products induces podocyte apoptosis and deletion through NADPH-dependent mechanisms. Kidney Int 76:1148–1160PubMedCrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.School of PharmacyAnhui Medical UniversityHefeiChina

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