Tubular overexpression of gremlin induces renal damage susceptibility in mice

Alejandra Droguett, Paola Krall, M. Eugenia Burgos, Graciela Valderrama, Daniel Carpio, Leopoldo Ardiles, Raquel Rodriguez-Diez, Bredford Kerr, Katherina Walz, Marta Ruiz-Ortega, Jesus Egido, Sergio Mezzano

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Article numbere101879
JournalPLoS One
Volume9
Issue number7
DOIs
StatePublished - Jul 18 2014
Externally publishedYes

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kidneys
Kidney
mice
kidney diseases
Lymphocytes
Macrophages
genetically modified organisms
Transgenic Mice
Folic Acid
Infiltration
Androgens
fibrosis
Allografts
Genes
Fibrosis
Proteinuria
diabetic nephropathy
glomerulonephritis
nephrotoxicity
allografting

ASJC Scopus subject areas

  • Medicine(all)
  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Droguett, A., Krall, P., Burgos, M. E., Valderrama, G., Carpio, D., Ardiles, L., ... Mezzano, S. (2014). Tubular overexpression of gremlin induces renal damage susceptibility in mice. PLoS One, 9(7), [e101879]. https://doi.org/10.1371/journal.pone.0101879

Tubular overexpression of gremlin induces renal damage susceptibility in mice. / Droguett, Alejandra; Krall, Paola; Burgos, M. Eugenia; Valderrama, Graciela; Carpio, Daniel; Ardiles, Leopoldo; Rodriguez-Diez, Raquel; Kerr, Bredford; Walz, Katherina; Ruiz-Ortega, Marta; Egido, Jesus; Mezzano, Sergio.

In: PLoS One, Vol. 9, No. 7, e101879, 18.07.2014.

Research output: Contribution to journalArticle

Droguett, A, Krall, P, Burgos, ME, Valderrama, G, Carpio, D, Ardiles, L, Rodriguez-Diez, R, Kerr, B, Walz, K, Ruiz-Ortega, M, Egido, J & Mezzano, S 2014, 'Tubular overexpression of gremlin induces renal damage susceptibility in mice', PLoS One, vol. 9, no. 7, e101879. https://doi.org/10.1371/journal.pone.0101879
Droguett A, Krall P, Burgos ME, Valderrama G, Carpio D, Ardiles L et al. Tubular overexpression of gremlin induces renal damage susceptibility in mice. PLoS One. 2014 Jul 18;9(7). e101879. https://doi.org/10.1371/journal.pone.0101879
Droguett, Alejandra ; Krall, Paola ; Burgos, M. Eugenia ; Valderrama, Graciela ; Carpio, Daniel ; Ardiles, Leopoldo ; Rodriguez-Diez, Raquel ; Kerr, Bredford ; Walz, Katherina ; Ruiz-Ortega, Marta ; Egido, Jesus ; Mezzano, Sergio. / Tubular overexpression of gremlin induces renal damage susceptibility in mice. In: PLoS One. 2014 ; Vol. 9, No. 7.
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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.",
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