title: Tubular overexpression of gremlin induces renal damage susceptibility in mice.
abstract: A growing number of patients are recognized worldwide to have chronic kidney disease. Glomerular and interstitial fibrosis are hallmarks of renal progression. However, fibrosis of the kidney remains an unresolved challenge, and its molecular mechanisms are still not fully understood. Gremlin is an embryogenic gene that has been shown to play a key role in nephrogenesis, and its expression is generally low in the normal adult kidney. However, gremlin expression is elevated in many human renal diseases, including diabetic nephropathy, pauci-immune glomerulonephritis and chronic allograft nephropathy. Several studies have proposed that gremlin may be involved in renal damage by acting as a downstream mediator of TGF-β. To examine the in vivo role of gremlin in kidney pathophysiology, we generated seven viable transgenic mouse lines expressing human gremlin (GREM1) specifically in renal proximal tubular epithelial cells under the control of an androgen-regulated promoter. These lines demonstrated 1.2- to 200-fold increased GREM1 expression. GREM1 transgenic mice presented a normal phenotype and were without proteinuria and renal function involvement. In response to the acute renal damage cause by folic acid nephrotoxicity, tubule-specific GREM1 transgenic mice developed increased proteinuria after 7 and 14 days compared with wild-type treated mice. At 14 days tubular lesions, such as dilatation, epithelium flattening and hyaline casts, with interstitial cell infiltration and mild fibrosis were significantly more prominent in transgenic mice than wild-type mice. Tubular GREM1 overexpression was correlated with the renal upregulation of profibrotic factors, such as TGF-β and αSMA, and with increased numbers of monocytes/macrophages and lymphocytes compared to wild-type mice. Taken together, our results suggest that GREM1-overexpressing mice have an increased susceptibility to renal damage, supporting the involvement of gremlin in renal damage progression. This transgenic mouse model could be used as a new tool for enhancing the knowledge of renal disease progression.
authors.affiliation: Division Nephrology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Droguett
authors.affiliation: Division Nephrology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Paola
authors.initials: P
authors.lastname: Krall
authors.affiliation: Division Nephrology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: Burgos
authors.affiliation: Division Nephrology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Graciela
authors.initials: G
authors.lastname: Valderrama
authors.affiliation: Hystopathology Division, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carpio
authors.affiliation: Division Nephrology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Ardiles
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodriguez-Diez
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile.
authors.forename: Bredford
authors.initials: B
authors.lastname: Kerr
authors.affiliation: Centro de Estudios Científicos, Valdivia, Chile.
authors.forename: Katherina
authors.initials: K
authors.lastname: Walz
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: Division Nephrology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
mesh_terms: D000818:Animals; D002460:Cell Line; D004198:Disease Susceptibility; D005492:Folic Acid / Q000009:adverse effects; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007684:Kidney Tubules / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D005492:Folic Acid