Inflammation and Fibrosis in Polycystic Kidney Disease

  • Cheng Jack Song
  • Kurt A. Zimmerman
  • Scott J. Henke
  • Bradley K. Yoder
Part of the Results and Problems in Cell Differentiation book series (RESULTS, volume 60)


Polycystic kidney disease (PKD) is a commonly inherited disorder characterized by cyst formation and fibrosis (Wilson, N Engl J Med 350:151–164, 2004) and is caused by mutations in cilia or cilia-related proteins, such as polycystin 1 or 2 (Oh and Katsanis, Development 139:443–448, 2012; Kotsis et al., Nephrol Dial Transplant 28:518–526, 2013). A major pathological feature of PKD is the development of interstitial inflammation and fibrosis with an associated accumulation of inflammatory cells (Grantham, N Engl J Med 359:1477–1485, 2008; Zeier et al., Kidney Int 42:1259–1265, 1992; Ibrahim, Sci World J 7:1757–1767, 2007). It is unclear whether inflammation is a driving force for cyst formation or a consequence of the pathology (Ta et al., Nephrology 18:317–330, 2013) as in some murine models cysts are present prior to the increase in inflammatory cells (Phillips et al., Kidney Blood Press Res 30:129–144, 2007; Takahashi et al., J Am Soc Nephrol JASN 1:980–989, 1991), while in other models the increase in inflammatory cells is present prior to or coincident with cyst initiation (Cowley et al., Kidney Int 43:522–534, 1993, Kidney Int 60:2087–2096, 2001). Additional support for inflammation as an important contributor to cystic kidney disease is the increased expression of many pro-inflammatory cytokines in murine models and human patients with cystic kidney disease (Karihaloo et al., J Am Soc Nephrol JASN 22:1809–1814, 2011; Swenson-Fields et al., Kidney Int, 2013; Li et al., Nat Med 14:863–868, 2008a). Based on these data, an emerging model in the field is that disruption of primary cilia on tubule epithelial cells leads to abnormal cytokine cross talk between the epithelium and the inflammatory cells contributing to cyst growth and fibrosis (Ta et al., Nephrology 18:317–330, 2013). These cytokines are produced by interstitial fibroblasts, inflammatory cells, and tubule epithelial cells and activate multiple pathways including the JAK-STAT and NF-κB signaling (Qin et al., J Am Soc Nephrol JASN 23:1309–1318, 2012; Park et al., Am J Nephrol 32:169–178, 2010; Bhunia et al., Cell 109:157–168, 2002). Indeed, inflammatory cells are responsible for producing several of the pro-fibrotic growth factors observed in PKD patients with fibrosis (Nakamura et al., Am J Nephrol 20:32–36, 2000; Wilson et al., J Cell Physiol 150:360–369, 1992; Song et al., Hum Mol Genet 18:2328–2343, 2009; Schieren et al., Nephrol Dial Transplant 21:1816–1824, 2006). These growth factors trigger epithelial cell proliferation and myofibroblast activation that stimulate the production of extracellular matrix (ECM) genes including collagen types 1 and 3 and fibronectin, leading to reduced glomerular function with approximately 50% of ADPKD patients progressing to end-stage renal disease (ESRD). Therefore, treatments designed to reduce inflammation and slow the rate of fibrosis are becoming important targets that hold promise to improve patient life span and quality of life. In fact, recent studies in several PKD mouse models indicate that depletion of macrophages reduces cyst severity. In this chapter, we review the potential mechanisms of interstitial inflammation in PKD with a focus on ADPKD and discuss the role of interstitial inflammation in progression to fibrosis and ESRD.


  1. Adams DO, Hamilton TA (1984) The cell biology of macrophage activation. Annu Rev Immunol 2:283–318PubMedCrossRefGoogle Scholar
  2. Albaqumi M, Srivastava S, Li Z, Zhdnova O, Wulff H, Itani O, Wallace DP, Skolnik EY (2008) KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease. Kidney Int 74:740–749PubMedCrossRefGoogle Scholar
  3. Basten SG, Giles RH (2013) Functional aspects of primary cilia in signaling, cell cycle and tumorigenesis. Cilia 2:6PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bastos AP, Piontek K, Silva AM, Martini D, Menezes LF, Fonseca JM, Fonseca II, Germino GG, Onuchic LF (2009) Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion. J Am Soc Nephrol JASN 20:2389–2402PubMedCrossRefGoogle Scholar
  5. Benoit M, Desnues B, Mege JL (2008) Macrophage polarization in bacterial infections. J Immunol 181:3733–3739PubMedCrossRefGoogle Scholar
  6. Bernhardt WM, Wiesener MS, Weidemann A, Schmitt R, Weichert W, Lechler P, Campean V, Ong AC, Willam C, Gretz N, Eckardt KU (2007) Involvement of hypoxia-inducible transcription factors in polycystic kidney disease. Am J Pathol 170:830–842PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu PN, Germino FJ, Germino GG (2002) PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell 109:157–168PubMedCrossRefGoogle Scholar
  8. Bonner JC (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 15:255–273PubMedCrossRefGoogle Scholar
  9. Boor P, Sebekova K, Ostendorf T, Floege J (2007) Treatment targets in renal fibrosis. Nephrol Dial Transplant 22:3391–3407PubMedCrossRefGoogle Scholar
  10. Bruhl H, Cihak J, Schneider MA, Plachy J, Rupp T, Wenzel I, Shakarami M, Milz S, Ellwart JW, Stangassinger M, Schlondorff D, Mack M (2004) Dual role of CCR2 during initiation and progression of collagen-induced arthritis: evidence for regulatory activity of CCR2+ T cells. J Immunol 172:890–898PubMedCrossRefGoogle Scholar
  11. Cabrera S, Gaxiola M, Arreola JL, Ramirez R, Jara P, D’Armiento J, Richards T, Selman M, Pardo A (2007) Overexpression of MMP9 in macrophages attenuates pulmonary fibrosis induced by bleomycin. Int J Biochem Cell Biol 39:2324–2338PubMedCrossRefGoogle Scholar
  12. Cao Q, Wang Y, Wang XM, Lu J, Lee VW, Ye Q, Nguyen H, Zheng G, Zhao Y, Alexander SI, Harris DC (2015) Renal F4/80+ CD11c+ mononuclear phagocytes display phenotypic and functional characteristics of macrophages in health and in adriamycin nephropathy. J Am Soc Nephrol JASN 26:349–363PubMedCrossRefGoogle Scholar
  13. Catania JM, Chen G, Parrish AR (2007) Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol Renal Physiol 292:F905–F911PubMedCrossRefGoogle Scholar
  14. Clements M, Gershenovich M, Chaber C, Campos-Rivera J, Du P, Zhang M, Ledbetter S, Zuk A (2015) Differential Ly6C expression after renal ischemia-reperfusion identifies unique macrophage populations. J Am Soc Nephrol JASN 27:159–170PubMedPubMedCentralCrossRefGoogle Scholar
  15. Cowley BD Jr, Gudapaty S, Kraybill AL, Barash BD, Harding MA, Calvet JP, Gattone VH 2nd (1993) Autosomal-dominant polycystic kidney disease in the rat. Kidney Int 43:522–534PubMedCrossRefGoogle Scholar
  16. Cowley BD Jr, Ricardo SD, Nagao S, Diamond JR (2001) Increased renal expression of monocyte chemoattractant protein-1 and osteopontin in ADPKD in rats. Kidney Int 60:2087–2096PubMedCrossRefGoogle Scholar
  17. Davenport JR, Watts AJ, Roper VC, Croyle MJ, van Groen T, Wyss JM, Nagy TR, Kesterson RA, Yoder BK (2007) Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol 17:1586–1594PubMedPubMedCentralCrossRefGoogle Scholar
  18. Dell KM, Nemo R, Sweeney WE Jr, Levin JI, Frost P, Avner ED (2001) A novel inhibitor of tumor necrosis factor-alpha converting enzyme ameliorates polycystic kidney disease. Kidney Int 60:1240–1248PubMedCrossRefGoogle Scholar
  19. Dell’Italia LJ, Husain A (2002) Dissecting the role of chymase in angiotensin II formation and heart and blood vessel diseases. Curr Opin Cardiol 17:374–379PubMedCrossRefGoogle Scholar
  20. Dinsmore C, Reiter JF (2016) Endothelial primary cilia inhibit atherosclerosis. EMBO Rep 17:156–166PubMedPubMedCentralCrossRefGoogle Scholar
  21. Du J, Wilson PD (1995) Abnormal polarization of EGF receptors and autocrine stimulation of cyst epithelial growth in human ADPKD. Am J Phys 269:C487–C495CrossRefGoogle Scholar
  22. Eddy AA (2009) Serine proteases, inhibitors and receptors in renal fibrosis. Thromb Haemost 101:656–664PubMedPubMedCentralGoogle Scholar
  23. Ehrhardt A, Ehrhardt GR, Guo X, Schrader JW (2002) Ras and relatives—job sharing and networking keep an old family together. Exp Hematol 30:1089–1106PubMedCrossRefGoogle Scholar
  24. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101:890–898PubMedPubMedCentralCrossRefGoogle Scholar
  25. 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
  26. Follonier Castella L, Gabbiani G, McCulloch CA, Hinz B (2010) Regulation of myofibroblast activities: calcium pulls some strings behind the scene. Exp Cell Res 316:2390–2401PubMedCrossRefGoogle Scholar
  27. Gardner KD Jr, Burnside JS, Elzinga LW, Locksley RM (1991) Cytokines in fluids from polycystic kidneys. Kidney Int 39:718–724PubMedCrossRefGoogle Scholar
  28. Geiger B, Bershadsky A, Pankov R, Yamada KM (2001) Transmembrane crosstalk between the extracellular matrix--cytoskeleton crosstalk. Nat Rev Mol Cell Biol 2:793–805PubMedCrossRefGoogle Scholar
  29. Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14:392–404PubMedCrossRefGoogle Scholar
  30. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845PubMedPubMedCentralCrossRefGoogle Scholar
  31. Ginhoux F, Schultze JL, Murray PJ, Ochando J, Biswas SK (2015) New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat Immunol 17:34–40CrossRefGoogle Scholar
  32. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964PubMedCrossRefGoogle Scholar
  33. Grantham JJ (2008) Clinical practice. Autosomal dominant polycystic kidney disease. N Engl J Med 359:1477–1485PubMedCrossRefGoogle Scholar
  34. Grantham JJ, Mulamalla S, Swenson-Fields KI (2011) Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol 7:556–566PubMedCrossRefGoogle Scholar
  35. Grgic I, Kiss E, Kaistha BP, Busch C, Kloss M, Sautter J, Muller A, Kaistha A, Schmidt C, Raman G, Wulff H, Strutz F, Grone HJ, Kohler R, Hoyer J (2009) Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels. Proc Natl Acad Sci USA 106:14518–14523PubMedPubMedCentralCrossRefGoogle Scholar
  36. Guay-Woodford LM (2003) Murine models of polycystic kidney disease: molecular and therapeutic insights. Am J Physiol Renal Physiol 285:F1034–F1049PubMedCrossRefGoogle Scholar
  37. Hassane S, Leonhard WN, van der Wal A, Hawinkels LJ, Lantinga-van Leeuwen IS, ten Dijke P, Breuning MH, de Heer E, Peters DJ (2010) Elevated TGFbeta-Smad signalling in experimental Pkd1 models and human patients with polycystic kidney disease. J Pathol 222:21–31PubMedGoogle Scholar
  38. Helm O, Held-Feindt J, Grage-Griebenow E, Reiling N, Ungefroren H, Vogel I, Kruger U, Becker T, Ebsen M, Rocken C, Kabelitz D, Schafer H, Sebens S (2014) Tumor-associated macrophages exhibit pro- and anti-inflammatory properties by which they impact on pancreatic tumorigenesis. Int J Cancer 135:843–861PubMedCrossRefGoogle Scholar
  39. Henderson NC, Mackinnon AC, Farnworth SL, Kipari T, Haslett C, Iredale JP, Liu FT, Hughes J, Sethi T (2008) Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am J Pathol 172:288–298PubMedPubMedCentralCrossRefGoogle Scholar
  40. Hochheiser K, Heuser C, Krause TA, Teteris S, Ilias A, Weisheit C, Hoss F, Tittel AP, Knolle PA, Panzer U, Engel DR, Tharaux PL, Kurts C (2013) Exclusive CX3CR1 dependence of kidney DCs impacts glomerulonephritis progression. J Clin Invest 123:4242–4254PubMedPubMedCentralCrossRefGoogle Scholar
  41. Hu MC, Piscione TD, Rosenblum ND (2003) Elevated SMAD1/beta-catenin molecular complexes and renal medullary cystic dysplasia in ALK3 transgenic mice. Development 130:2753–2766PubMedCrossRefGoogle Scholar
  42. Huen SC, Cantley LG (2015) Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr Nephrol 30:199–209PubMedCrossRefGoogle Scholar
  43. Hull TD, Kamal AI, Boddu R, Bolisetty S, Guo L, Tisher CC, Rangarajan S, Chen B, Curtis LM, George JF, Agarwal A (2015) Heme oxygenase-1 regulates myeloid cell trafficking in AKI. J Am Soc Nephrol JASN 26:2139–2151PubMedCrossRefGoogle Scholar
  44. Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176:85–97PubMedPubMedCentralCrossRefGoogle Scholar
  45. Ibrahim S (2007) Increased apoptosis and proliferative capacity are early events in cyst formation in autosomal-dominant, polycystic kidney disease. Sci World J 7:1757–1767CrossRefGoogle Scholar
  46. Jena N, Martin-Seisdedos C, McCue P, Croce CM (1997) BMP7 null mutation in mice: developmental defects in skeleton, kidney, and eye. Exp Cell Res 230:28–37PubMedCrossRefGoogle Scholar
  47. Joly D, Morel V, Hummel A, Ruello A, Nusbaum P, Patey N, Noel LH, Rousselle P, Knebelmann B (2003) Beta4 integrin and laminin 5 are aberrantly expressed in polycystic kidney disease: role in increased cell adhesion and migration. Am J Pathol 163:1791–1800PubMedPubMedCentralCrossRefGoogle Scholar
  48. Karihaloo A, Koraishy F, Huen SC, Lee Y, Merrick D, Caplan MJ, Somlo S, Cantley LG (2011) Macrophages promote cyst growth in polycystic kidney disease. J Am Soc Nephrol JASN 22:1809–1814PubMedCrossRefGoogle Scholar
  49. Kaspareit-Rittinghausen J, Rapp K, Deerberg F, Wcislo A, Messow C (1989) Hereditary polycystic kidney disease associated with osteorenal syndrome in rats. Vet Pathol 26:195–201PubMedCrossRefGoogle Scholar
  50. Katz SI, Tamaki K, Sachs DH (1979) Epidermal Langerhans cells are derived from cells originating in bone marrow. Nature 282:324–326PubMedCrossRefGoogle Scholar
  51. Kotsis F, Boehlke C, Kuehn EW (2013) The ciliary flow sensor and polycystic kidney disease. Nephrol Dial Transplant 28:518–526PubMedPubMedCentralCrossRefGoogle Scholar
  52. Kratochvill F, Neale G, Haverkamp JM, Van de Velde LA, Smith AM, Kawauchi D, McEvoy J, Roussel MF, Dyer MA, Qualls JE, Murray PJ (2015) TNF counterbalances the emergence of M2 tumor macrophages. Cell Rep 12:1902–1914PubMedPubMedCentralCrossRefGoogle Scholar
  53. Kuo NT, Norman JT, Wilson PD (1997) Acidic FGF regulation of hyperproliferation of fibroblasts in human autosomal dominant polycystic kidney disease. Biochem Mol Med 61:178–191PubMedCrossRefGoogle Scholar
  54. Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, Jung S, Amit I (2014) Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159:1312–1326PubMedPubMedCentralCrossRefGoogle Scholar
  55. LeBleu VS, Taduri G, O’Connell J, Teng Y, Cooke VG, Woda C, Sugimoto H, Kalluri R (2013) Origin and function of myofibroblasts in kidney fibrosis. Nat Med 19:1047–1053PubMedPubMedCentralCrossRefGoogle Scholar
  56. Lee K, Boctor S, Barisoni LM, Gusella GL (2015) Inactivation of integrin-beta1 prevents the development of polycystic kidney disease after the loss of polycystin-1. J Am Soc Nephrol JASN 26:888–895PubMedCrossRefGoogle Scholar
  57. Leonhard WN, Kunnen SJ, Plugge AJ, Pasternack A, Jianu SB, Veraar K, El Bouazzaoui F, Hoogaars WM, Ten Dijke P, Breuning MH, De Heer E, Ritvos O, Peters DJ (2016) Inhibition of activin signaling slows progression of polycystic kidney disease. J Am Soc Nephrol JASN 27:3589–3599PubMedPubMedCentralCrossRefGoogle Scholar
  58. Li L, Huang L, Sung SS, Vergis AL, Rosin DL, Rose CE Jr, Lobo PI, Okusa MD (2008b) The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int 74:1526–1537PubMedPubMedCentralCrossRefGoogle Scholar
  59. Li X, Magenheimer BS, Xia S, Johnson T, Wallace DP, Calvet JP, Li R (2008a) A tumor necrosis factor-alpha-mediated pathway promoting autosomal dominant polycystic kidney disease. Nat Med 14:863–868PubMedPubMedCentralCrossRefGoogle Scholar
  60. 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 183:6733–6743PubMedCrossRefGoogle Scholar
  61. Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LS, Somlo S, Igarashi P (2003) Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci USA 100:5286–5291PubMedPubMedCentralCrossRefGoogle Scholar
  62. Liu D, Wang CJ, Judge DP, Halushka MK, Ni J, Habashi JP, Moslehi J, Bedja D, Gabrielson KL, Xu H, Qian F, Huso D, Dietz HC, Germino GG, Watnick T (2014) A Pkd1-Fbn1 genetic interaction implicates TGF-beta signaling in the pathogenesis of vascular complications in autosomal dominant polycystic kidney disease. J Am Soc Nephrol JASN 25:81–91PubMedCrossRefGoogle Scholar
  63. Low SH, Vasanth S, Larson CH, Mukherjee S, Sharma N, Kinter MT, Kane ME, Obara T, Weimbs T (2006) Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Dev Cell 10:57–69PubMedCrossRefGoogle Scholar
  64. Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S (2013) Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet 45:1004–1012PubMedPubMedCentralCrossRefGoogle Scholar
  65. Maeshima A, Yamashita S, Maeshima K, Kojima I, Nojima Y (2003) Activin a produced by ureteric bud is a differentiation factor for metanephric mesenchyme. J Am Soc Nephrol JASN 14:1523–1534PubMedCrossRefGoogle Scholar
  66. Mangos S, Lam PY, Zhao A, Liu Y, Mudumana S, Vasilyev A, Liu A, Drummond IA (2010) The ADPKD genes pkd1a/b and pkd2 regulate extracellular matrix formation. Dis Model Mech 3:354–365PubMedPubMedCentralCrossRefGoogle Scholar
  67. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549–555PubMedCrossRefGoogle Scholar
  68. McPherson EA, Luo Z, Brown RA, LeBard LS, Corless CC, Speth RC, Bagby SP (2004) Chymase-like angiotensin II-generating activity in end-stage human autosomal dominant polycystic kidney disease. J Am Soc Nephrol JASN 15:493–500PubMedCrossRefGoogle Scholar
  69. Merad M, Manz MG, Karsunky H, Wagers A, Peters W, Charo I, Weissman IL, Cyster JG, Engleman EG (2002) Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol 3:1135–1141PubMedPubMedCentralCrossRefGoogle Scholar
  70. Metcalf D, Mifsud S, Di Rago L, Nicola NA, Hilton DJ, Alexander WS (2002) Polycystic kidneys and chronic inflammatory lesions are the delayed consequences of loss of the suppressor of cytokine signaling-1 (SOCS-1). Proc Natl Acad Sci USA 99:943–948PubMedPubMedCentralCrossRefGoogle Scholar
  71. Mrug M, Zhou J, Woo Y, Cui X, Szalai AJ, Novak J, Churchill GA, Guay-Woodford LM (2008) Overexpression of innate immune response genes in a model of recessive polycystic kidney disease. Kidney Int 73:63–76PubMedCrossRefGoogle Scholar
  72. Nadel JA (1991) Biology of mast cell tryptase and chymase. Ann N Y Acad Sci 629:319–331PubMedCrossRefGoogle Scholar
  73. Nakamura T, Ebihara I, Fukui M, Osada S, Tomino Y, Masaki T, Goto K, Furuichi Y, Koide H (1993) Increased endothelin and endothelin receptor mRNA expression in polycystic kidneys of cpk mice. J Am Soc Nephrol JASN 4:1064–1072PubMedGoogle Scholar
  74. Nakamura T, Ushiyama C, Suzuki S, Ebihara I, Shimada N, Koide H (2000) Elevation of serum levels of metalloproteinase-1, tissue inhibitor of metalloproteinase-1 and type IV collagen, and plasma levels of metalloproteinase-9 in polycystic kidney disease. Am J Nephrol 20:32–36PubMedCrossRefGoogle Scholar
  75. Nelson PJ, Rees AJ, Griffin MD, Hughes J, Kurts C, Duffield J (2012) The renal mononuclear phagocytic system. J Am Soc Nephrol JASN 23:194–203PubMedCrossRefGoogle Scholar
  76. Nishida M, Okumura Y, Fujimoto S, Shiraishi I, Itoi T, Hamaoka K (2005) Adoptive transfer of macrophages ameliorates renal fibrosis in mice. Biochem Biophys Res Commun 332:11–16PubMedCrossRefGoogle Scholar
  77. Norman J (2011) Fibrosis and progression of autosomal dominant polycystic kidney disease (ADPKD). Biochim Biophys Acta 1812:1327–1336PubMedPubMedCentralCrossRefGoogle Scholar
  78. O’Leary CA, Mackay BM, Malik R, Edmondston JE, Robinson WF, Huxtable CR (1999) Polycystic kidney disease in bull terriers: an autosomal dominant inherited disorder. Aust Vet J 77:361–366PubMedCrossRefGoogle Scholar
  79. Obermuller N, Morente N, Kranzlin B, Gretz N, Witzgall R (2001) A possible role for metalloproteinases in renal cyst development. Am J Physiol Renal Physiol 280:F540–F550PubMedCrossRefGoogle Scholar
  80. Oh EC, Katsanis N (2012) Cilia in vertebrate development and disease. Development 139:443–448PubMedPubMedCentralCrossRefGoogle Scholar
  81. Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18:6853–6866PubMedCrossRefGoogle Scholar
  82. Park EY, Seo MJ, Park JH (2010) Effects of specific genes activating RAGE on polycystic kidney disease. Am J Nephrol 32:169–178PubMedCrossRefGoogle Scholar
  83. Patel V, Li L, Cobo-Stark P, Shao X, Somlo S, Lin F, Igarashi P (2008) Acute kidney injury and aberrant planar cell polarity induce cyst formation in mice lacking renal cilia. Hum Mol Genet 17:1578–1590PubMedPubMedCentralCrossRefGoogle Scholar
  84. Phillips JK, Hopwood D, Loxley RA, Ghatora K, Coombes JD, Tan YS, Harrison JL, McKitrick DJ, Holobotvskyy V, Arnolda LF, Rangan GK (2007) Temporal relationship between renal cyst development, hypertension and cardiac hypertrophy in a new rat model of autosomal recessive polycystic kidney disease. Kidney Blood Press Res 30:129–144PubMedCrossRefGoogle Scholar
  85. Piontek K, Menezes LF, Garcia-Gonzalez MA, Huso DL, Germino GG (2007) A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat Med 13:1490–1495PubMedPubMedCentralCrossRefGoogle Scholar
  86. Pollard JW (2009) Trophic macrophages in development and disease. Nat Rev Immunol 9:259–270PubMedPubMedCentralCrossRefGoogle Scholar
  87. Prasad S, McDaid JP, Tam FW, Haylor JL, Ong AC (2009) Pkd2 dosage influences cellular repair responses following ischemia-reperfusion injury. Am J Pathol 175:1493–1503PubMedPubMedCentralCrossRefGoogle Scholar
  88. Qi W, Chen X, Poronnik P, Pollock CA (2006) The renal cortical fibroblast in renal tubulointerstitial fibrosis. Int J Biochem Cell Biol 38:1–5PubMedCrossRefGoogle Scholar
  89. Qin S, Taglienti M, Cai L, Zhou J, Kreidberg JA (2012) c-Met and NF-kappaB-dependent overexpression of Wnt7a and -7b and Pax2 promotes cystogenesis in polycystic kidney disease. J Am Soc Nephrol JASN 23:1309–1318PubMedCrossRefGoogle Scholar
  90. Rae F, Woods K, Sasmono T, Campanale N, Taylor D, Ovchinnikov DA, Grimmond SM, Hume DA, Ricardo SD, Little MH (2007) Characterisation and trophic functions of murine embryonic macrophages based upon the use of a Csf1r-EGFP transgene reporter. Dev Biol 308:232–246PubMedPubMedCentralCrossRefGoogle Scholar
  91. Rankin CA, Suzuki K, Itoh Y, Ziemer DM, Grantham JJ, Calvet JP, Nagase H (1996) Matrix metalloproteinases and TIMPS in cultured C57BL/6J-cpk kidney tubules. Kidney Int 50:835–844PubMedCrossRefGoogle Scholar
  92. Ritvos O, Tuuri T, Eramaa M, Sainio K, Hilden K, Saxen L, Gilbert SF (1995) Activin disrupts epithelial branching morphogenesis in developing glandular organs of the mouse. Mech Dev 50:229–245PubMedCrossRefGoogle Scholar
  93. Schaefer L, Han X, Gretz N, Hafner C, Meier K, Matzkies F, Schaefer RM (1996) Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat. Kidney Int 49:75–81PubMedCrossRefGoogle Scholar
  94. Schieren G, Rumberger B, Klein M, Kreutz C, Wilpert J, Geyer M, Faller D, Timmer J, Quack I, Rump LC, Walz G, Donauer J (2006) Gene profiling of polycystic kidneys. Nephrol Dial Transplant 21:1816–1824PubMedCrossRefGoogle Scholar
  95. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW, Frampton J, Liu KJ, Geissmann F (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90PubMedCrossRefGoogle Scholar
  96. Shannon MB, Patton BL, Harvey SJ, Miner JH (2006) A hypomorphic mutation in the mouse laminin alpha5 gene causes polycystic kidney disease. J Am Soc Nephrol JASN 17:1913–1922PubMedCrossRefGoogle Scholar
  97. Sharma N, Malarkey EB, Berbari NF, O’Connor AK, Vanden Heuvel GB, Mrug M, Yoder BK (2013) Proximal tubule proliferation is insufficient to induce rapid cyst formation after cilia disruption. J Am Soc Nephrol JASN 24:456–464PubMedPubMedCentralCrossRefGoogle Scholar
  98. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795PubMedPubMedCentralCrossRefGoogle Scholar
  99. Snelgrove RJ, Jackson PL, Hardison MT, Noerager BD, Kinloch A, Gaggar A, Shastry S, Rowe SM, Shim YM, Hussell T, Blalock JE (2010) A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science 330:90–94PubMedPubMedCentralCrossRefGoogle Scholar
  100. Song X, Di Giovanni V, He N, Wang K, Ingram A, Rosenblum ND, Pei Y (2009) Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks. Hum Mol Genet 18:2328–2343PubMedCrossRefGoogle Scholar
  101. Stables MJ, Shah S, Camon EB, Lovering RC, Newson J, Bystrom J, Farrow S, Gilroy DW (2011) Transcriptomic analyses of murine resolution-phase macrophages. Blood 118:e192–e208PubMedPubMedCentralCrossRefGoogle Scholar
  102. Swenson-Fields KI, Vivian CJ, Salah SM, Peda JD, Davis BM, van Rooijen N, Wallace DP, Fields TA (2013) Macrophages promote polycystic kidney disease progression. Kidney Int 83:855–864PubMedPubMedCentralCrossRefGoogle Scholar
  103. Ta MH, Harris DC, Rangan GK (2013) Role of interstitial inflammation in the pathogenesis of polycystic kidney disease. Nephrology 18:317–330PubMedCrossRefGoogle Scholar
  104. Takahashi H, Calvet JP, Dittemore-Hoover D, Yoshida K, Grantham JJ, Gattone VH 2nd (1991) A hereditary model of slowly progressive polycystic kidney disease in the mouse. J Am Soc Nephrol JASN 1:980–989PubMedGoogle Scholar
  105. Takakura A, Contrino L, Zhou X, Bonventre JV, Sun Y, Humphreys BD, Zhou J (2009) Renal injury is a third hit promoting rapid development of adult polycystic kidney disease. Hum Mol Genet 18:2523–2531PubMedPubMedCentralCrossRefGoogle Scholar
  106. Talbot JJ, Song X, Wang X, Rinschen MM, Doerr N, LaRiviere WB, Schermer B, Pei YP, Torres VE, Weimbs T (2014) The cleaved cytoplasmic tail of polycystin-1 regulates Src-dependent STAT3 activation. J Am Soc Nephrol JASN 25:1737–1748PubMedCrossRefGoogle Scholar
  107. Togawa H, Nakanishi K, Mukaiyama H, Hama T, Shima Y, Sako M, Miyajima M, Nozu K, Nishii K, Nagao S, Takahashi H, Iijima K, Yoshikawa N (2011) Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease. Am J Physiol Renal Physiol 300:F511–F520PubMedCrossRefGoogle Scholar
  108. van Furth R, Cohn ZA (1968) The origin and kinetics of mononuclear phagocytes. J Exp Med 128:415–435PubMedPubMedCentralCrossRefGoogle Scholar
  109. Vernon MA, Mylonas KJ, Hughes J (2010) Macrophages and renal fibrosis. Semin Nephrol 30:302–317PubMedCrossRefGoogle Scholar
  110. Vilayur E, Harris DC (2009) Emerging therapies for chronic kidney disease: what is their role? Nat Rev Nephrol 5:375–383PubMedCrossRefGoogle Scholar
  111. Vogler C, Homan S, Pung A, Thorpe C, Barker J, Birkenmeier EH, Upadhya P (1999) Clinical and pathologic findings in two new allelic murine models of polycystic kidney disease. J Am Soc Nephrol JASN 10:2534–2539PubMedGoogle Scholar
  112. Wallace DP, White C, Savinkova L, Nivens E, Reif GA, Pinto CS, Raman A, Parnell SC, Conway SJ, Fields TA (2014) Periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney disease. Kidney Int 85:845–854PubMedCrossRefGoogle Scholar
  113. Wann AK, Knight MM (2012) Primary cilia elongation in response to interleukin-1 mediates the inflammatory response. Cell Mol Life Sci 69:2967–2977PubMedPubMedCentralCrossRefGoogle Scholar
  114. Wann AK, Chapple JP, Knight MM (2014) The primary cilium influences interleukin-1beta-induced NFkappaB signalling by regulating IKK activity. Cell Signal 26:1735–1742PubMedPubMedCentralCrossRefGoogle Scholar
  115. Weimbs T, Talbot JJ (2013) STAT3 signaling in polycystic kidney disease. Drug Discov Today Dis Mech 10:e113–e118PubMedPubMedCentralCrossRefGoogle Scholar
  116. Wilson PD (2004) Polycystic kidney disease. N Engl J Med 350:151–164PubMedCrossRefGoogle Scholar
  117. Wilson PD (2008) Mouse models of polycystic kidney disease. Curr Top Dev Biol 84:311–350PubMedCrossRefGoogle Scholar
  118. Wilson PD, Burrow CR (1999) Cystic diseases of the kidney: role of adhesion molecules in normal and abnormal tubulogenesis. Exp Nephrol 7:114–124PubMedCrossRefGoogle Scholar
  119. Wilson PD, Falkenstein D (1995) The pathology of human renal cystic disease. Curr Top Pathol 88:1–50PubMedCrossRefGoogle Scholar
  120. Wilson PD, Goilav B (2007) Cystic disease of the kidney. Annu Rev Pathol 2:341–368PubMedCrossRefGoogle Scholar
  121. Wilson PD, Sherwood AC (1991) Tubulocystic epithelium. Kidney Int 39:450–463PubMedCrossRefGoogle Scholar
  122. Wilson PD, Geng L, Li X, Burrow CR (1999) The PKD1 gene product, “polycystin-1,” is a tyrosine-phosphorylated protein that colocalizes with alpha2beta1-integrin in focal clusters in adherent renal epithelia. Lab Invest J Tech Methods Pathol 79:1311–1323Google Scholar
  123. Wilson PD, Hreniuk D, Gabow PA (1992) Abnormal extracellular matrix and excessive growth of human adult polycystic kidney disease epithelia. J Cell Physiol 150:360–369PubMedCrossRefGoogle Scholar
  124. Wozniak MA, Modzelewska K, Kwong L, Keely PJ (2004) Focal adhesion regulation of cell behavior. Biochim Biophys Acta 1692:103–119PubMedCrossRefGoogle Scholar
  125. Wynn TA, Barron L (2010) Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 30:245–257PubMedPubMedCentralCrossRefGoogle Scholar
  126. Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496:445–455PubMedPubMedCentralCrossRefGoogle Scholar
  127. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, Gohel TD, Emde M, Schmidleithner L, Ganesan H, Nino-Castro A, Mallmann MR, Labzin L, Theis H, Kraut M, Beyer M, Latz E, Freeman TC, Ulas T, Schultze JL (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40:274–288PubMedPubMedCentralCrossRefGoogle Scholar
  128. Yamashita S, Maeshima A, Kojima I, Nojima Y (2004) Activin A is a potent activator of renal interstitial fibroblasts. J Am Soc Nephrol JASN 15:91–101PubMedCrossRefGoogle Scholar
  129. Yoder BK (2007) Role of primary cilia in the pathogenesis of polycystic kidney disease. J Am Soc Nephrol JASN 18:1381–1388PubMedCrossRefGoogle Scholar
  130. Yoder BK, Hou X, Guay-Woodford LM (2002) The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol JASN 13:2508–2516PubMedCrossRefGoogle Scholar
  131. Yoder BK, Richards WG, Sweeney WE, Wilkinson JE, Avener ED, Woychik RP (1995) Insertional mutagenesis and molecular analysis of a new gene associated with polycystic kidney disease. Proc Assoc Am Physicians 107:314–323PubMedGoogle Scholar
  132. Zeier M, Fehrenbach P, Geberth S, Mohring K, Waldherr R, Ritz E (1992) Renal histology in polycystic kidney disease with incipient and advanced renal failure. Kidney Int 42:1259–1265PubMedCrossRefGoogle Scholar
  133. Zeisberg M, Neilson EG (2010) Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol JASN 21:1819–1834PubMedCrossRefGoogle Scholar
  134. Zeltner R, Hilgers KF, Schmieder RE, Porst M, Schulze BD, Hartner A (2008) A promoter polymorphism of the alpha 8 integrin gene and the progression of autosomal-dominant polycystic kidney disease. Nephron Clin Pract 108:c169–c175PubMedCrossRefGoogle Scholar
  135. Zheng D, Wolfe M, Cowley BD Jr, Wallace DP, Yamaguchi T, Grantham JJ (2003) Urinary excretion of monocyte chemoattractant protein-1 in autosomal dominant polycystic kidney disease. J Am Soc Nephrol JASN 14:2588–2595PubMedCrossRefGoogle Scholar
  136. Zimmerman K, Yoder BK (2015) SnapShot: sensing and signaling by cilia. Cell 161(692–692):e691Google Scholar
  137. Zoja C, Corna D, Locatelli M, Rottoli D, Pezzotta A, Morigi M, Zanchi C, Buelli S, Guglielmotti A, Perico N, Remuzzi A, Remuzzi G (2015) Effects of MCP-1 inhibition by bindarit therapy in a rat model of polycystic kidney disease. Nephron 129:52–61PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2017

Open Access This chapter is distributed under the terms of the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Authors and Affiliations

  • Cheng Jack Song
    • 1
  • Kurt A. Zimmerman
    • 1
  • Scott J. Henke
    • 1
  • Bradley K. Yoder
    • 1
  1. 1.Department of Cell, Developmental and Integrative BiologyUniversity of Alabama at BirminghamBirminghamUSA

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