Gremlin is a downstream profibrotic mediator of transforming growth factor-beta in cultured renal cells

Nephron - Experimental Nephrology

Volumn 122, Issue 1-2, 2013, Pages 62-74

  Rodrigues Diez, Raquel ^a   Lavoz, Carolina ^a   Carvajal, Gisselle ^a   Rayego Mateos, Sandra ^a   Diez, Raul R Rodrigues ^a   Ortiz, Alberto ^b   Egido, Jesús ^c   Mezzano, Sergio ^d   Ruiz Ortega, Marta ^a  

^a Fundación Jiménez Díaz   (Spain)

^b Dialysis Unit   (Spain)

^c UNIVERSIDAD AUTÓNOMA DE MADRID   (Spain)

^d UNIVERSIDAD AUSTRAL DE CHILE   (Chile)

Author keywords

Epithelial mesenchymal transition; Gremlin; Renal fibrosis; Transforming growth factor beta

Indexed keywords

COLLAGEN TYPE 1; CYTOKERATIN; FIBRONECTIN; GELATINASE B; GREMLIN; MEMBRANE PROTEIN; RECOMBINANT PROTEIN; SMALL INTERFERING RNA; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG; UVOMORULIN;

ANIMAL CELL; ARTICLE; CELL PROLIFERATION; CONFOCAL MICROSCOPY; CONTROLLED STUDY; DOWN REGULATION; EPITHELIAL MESENCHYMAL TRANSITION; EXTRACELLULAR MATRIX; FIBROBLAST; HUMAN; HUMAN CELL; INHIBITION KINETICS; KIDNEY CELL CULTURE; KIDNEY EPITHELIUM; KIDNEY FIBROSIS; KIDNEY TUBULE CELL; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN FUNCTION; REAL TIME POLYMERASE CHAIN REACTION; UPREGULATION; WESTERN BLOTTING;

ANIMALS; CELL LINE; CELLS, CULTURED; EPITHELIAL CELLS; EPITHELIAL-MESENCHYMAL TRANSITION; FIBROBLASTS; FIBROSIS; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; KIDNEY; MICE; RNA, SMALL INTERFERING; TRANSFORMING GROWTH FACTOR BETA;

EID: 84875646745     PISSN: None     EISSN: 16602129     Source Type: Journal    
DOI: 10.1159/000346575     Document Type: Article

References (26)

1. Zeisberg M, Neilson EG: Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol 2010; 21: 1819-1834.
2. Liu Y: New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 2010; 21: 212-222.
3. McMahon R, Murphy M, Clarkson M, Taal M, Mackenzie HS, Godson C, Martin F, Brady HR: IHG-2, a mesangial cell gene induced by high glucose, is human gremlin. Regulation by extracellular glucose concentration, cyclic mechanical strain, and transforming growth factor-beta1. J Biol Chem 2000; 275: 9901-9904.
4. Topol LZ, Marx M, Laugier D, Bogdanova NN, Boubnov NV, Clausen PA, Calothy G, Blair DG: Identification of drm, a novel gene whose expression is suppressed in transformed cells and which can inhibit growth of normal but not transformed cells in culture. Mol Cell Biol 1997; 17: 4801-4810.
5. Michos O, Panman L, Vintersten K, Beier K, Zeller R, Zuniga A: Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development 2004; 131: 3401-3410.
6. Dolan V, Murphy M, Sadlier D, Lappin D, Doran P, Godson C, Martin F, O'Meara Y, Schmid H, Henger A, Kretzler M, Droguett A, Mezzano S, Brady HR: Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy. Am J Kidney Dis 2005; 45: 1034-1039.
7. Roxburgh SA, Kattla JJ, Curran SP, O'Meara YM, Pollock CA, Goldschmeding R, Godson C, Martin F, Brazil DP: Allelic depletion of grem1 attenuates diabetic kidney disease. Diabetes 2009; 58: 1641-1650.
8. Zhang Q, Shi Y, Wada J, Malakauskas SM, Liu M, Ren Y, Du C, Duan H, Li Y, Li Y, Zhang Y: In vivo delivery of Gremlin siRNA plasmid reveals therapeutic potential against diabetic nephropathy by recovering bone morphogenetic protein-7. PLoS One 2010; 22; 5:e11709.
9. Farkas L, Farkas D, Gauldie J, Warburton D, Shi W, Kolb M: Transient overexpression of Gremlin results in epithelial activation and reversible fibrosis in rat lungs. Am J Respir Cell Mol Biol 2010; 44: 870-878.
10. Alvarez RJ, Sun MJ, Haverty TP, Iozzo RV, Myers JC, Neilson EG: Biosynthetic and proliferative characteristics of tubulointerstitial fibroblasts probed with paracrine cytokines. Kidney Int 1992; 41: 14-23.
11. Carvajal G, Rodriguez-Vita J, Rodrigues-Diez R, Sanchez-Lopez E, Ruperez M, Cartier C, Esteban V, Ortiz A, Egido J, Mezzano SA, Ruiz-Ortega M: Angiotensin II activates the Smad pathway during epithelial mesenchymal transdifferentiation. Kidney Int 2008; 74: 585-595.
12. Zeisberg M, Neilson EG: Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009; 119: 1429-1437.
13. Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, Neilson EG: Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 1995; 130: 393-405.
14. Boers W, Aarrass S, Linthorst C, Pinzani M, Elferink RO, Bosma P: Transcriptional profiling reveals novel markers of liver fibrogenesis: gremlin and insulin-like growth factor-binding proteins. J Biol Chem 2006; 16; 281: 16289-16295.
15. Costello CM, Cahill E, Martin F, Gaine S, McLoughlin P: Role of gremlin in the lung: development and disease. Am J Respir Cell Mol Biol 2010; 42: 517-523.
16. Namkoong H, Shin SM, Kim HK, Ha SA, Cho GW, Hur SY, Kim TE, Kim JW: The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein. BMC Cancer 2006; 18; 6: 74.
17. Zode GS, Clark AF, Wordinger RJ: Bone morphogenetic protein 4 inhibits TGF-beta2 stimulation of extracellular matrix proteins in optic nerve head cells: role of gremlin in ECM modulation. Glia 2009; 57: 755-766.
18. Moustakas A, Heldin CH: Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci 2007; 98: 1512-1520.
19. Mezzano S, Droguett A, Eugenia Burgos M, Aros C, Ardiles L, Flores C, Carpio D, Carvajal G, Ruiz-Ortega M, Egido J: Expression of gremlin, a bone morphogenetic protein antagonist, in glomerular crescents of pauci-immune glomerulonephritis. Nephrol Dial Transplant 2007; 22: 1882-1890.
20. Cahill E, Costello CM, Rowan SC, Harkin S, Howell K, Leonard MO, Southwood M, Cummins EP, Fitzpatrick SF, Taylor CT, Morrell NW, Martin F, McLoughlin P: Gremlin plays a key role in the pathogenesis of pulmonary hypertension. Circulation 2012; 125: 920-930.
21. Myllarniemi M, Lindholm P, Ryynanen MJ, Kliment CR, Salmenkivi K, Keski-Oja J, Kinnula VL, Oury TD, Koli K: Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis. Am J Respir Crit Care Med. 2008; 177: 321-329.
22. Li Y, Wang Z, Wang S, Zhao J, Zhang J, Huang Y: Gremlin-mediated decrease in bone morphogenetic protein signaling promotes aristolochic acid-induced epithelial-tomesenchymal transition (EMT) in HK-2 cells. Toxicology. 2012; 297: 68-75.
23. Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R: BMP-7 counteracts TGF-beta1-induced epithelialto-mesenchymal transition and reverses chronic renal injury. Nat Med 2003; 9: 964-968.
24. Yang YL, Ju HZ, Liu SF, Lee TC, Shih YW, Chuang LY, Guh JY, Yang YY, Liao TN, Hung TJ, Hung MY: BMP-2 suppresses renal interstitial fibrosis by regulating epithelial-mesenchymal transition. J Cell Biochem 2011; 112: 2558-2565.
25. Chen B, Athanasiou M, Gu Q, Blair DG: Drm/Gremlin transcriptionally activates p21(Cip1) via a novel mechanism and inhibits neoplastic transformation. Biochem Biophys Res Commun 2002; 295: 1135-1141.
26. Mitola S, Ravelli C, Moroni E, Salvi V, Leali D, Ballmer-Hofer K, Zammataro L, Presta M: Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2. Blood 2010; 116: 3677-3680.