title: Tubular overexpression of Gremlin in transgenic mice aggravates renal damage in diabetic nephropathy.
abstract: Diabetic nephropathy (DN) is currently a leading cause of end-stage renal failure worldwide. Gremlin was identified as a gene differentially expressed in mesangial cells exposed to high glucose and in experimental diabetic kidneys. We have described that Gremlin is highly expressed in biopsies from patients with diabetic nephropathy, predominantly in areas of tubulointerstitial fibrosis. In streptozotocin (STZ)-induced experimental diabetes, Gremlin deletion using Grem1 heterozygous knockout mice or by gene silencing, ameliorates renal damage. To study the in vivo role of Gremlin in renal damage, we developed a diabetic model induced by STZ in transgenic (TG) mice expressing human Gremlin in proximal tubular epithelial cells. The albuminuria/creatinuria ratio, determined at week 20 after treatment, was significantly increased in diabetic mice but with no significant differences between transgenic (TG/STZ) and wild-type mice (WT/STZ). To assess the level of renal damage, kidney tissue was analyzed by light microscopy (periodic acid-Schiff and Masson staining), electron microscopy, and quantitative PCR. TG/STZ mice had significantly greater thickening of the glomerular basement membrane, increased mesangial matrix, and podocytopenia vs. WT/STZ. At the tubulointerstitial level, TG/STZ showed increased cell infiltration and mild interstitial fibrosis. In addition, we observed a decreased expression of podocin and overexpression of monocyte chemoattractant protein-1 and fibrotic-related markers, including transforming growth factor-β1, Col1a1, and α-smooth muscle actin. Together, these results show that TG mice overexpressing Gremlin in renal tubules develop greater glomerular and tubulointerstitial injury in response to diabetic-mediated damage and support the involvement of Gremlin in diabetic nephropathy.
authors.affiliation: Nephrology Division, School of Medicine, Universidad Austral de Chile, Valdivia, Chile;
authors.forename: Vanessa
authors.initials: V
authors.lastname: Marchant
authors.affiliation: Nephrology Division, School of Medicine, Universidad Austral de Chile, Valdivia, Chile;
authors.forename: Alejandra
authors.initials: A
authors.lastname: Droguett
authors.affiliation: Nephrology Division, School of Medicine, Universidad Austral de Chile, Valdivia, Chile;
authors.forename: Graciela
authors.initials: G
authors.lastname: Valderrama
authors.affiliation: Nephrology Division, School of Medicine, Universidad Austral de Chile, Valdivia, Chile;
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: Burgos
authors.affiliation: Nephrology Division, School of Medicine, Universidad Austral de Chile, Valdivia, Chile;
authors.forename: Daniel
authors.initials: D
authors.lastname: Carpio
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile;
authors.forename: Bredford
authors.initials: B
authors.lastname: Kerr
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria (IIS)-Fundación Jimenez Diaz, Madrid, Spain; and.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-UAM/Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.affiliation: Nephrology Division, School of Medicine, Universidad Austral de Chile, Valdivia, Chile; smezzano@uach.cl.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics*; D007678:Kidney Glomerulus / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009395:Nephritis, Interstitial / Q000473:pathology; D050199:Podocytes / Q000473:pathology
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins
keywords: Gremlin; diabetic nephropathy