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.
Highlights
Kidney disease and renal failure are worldwide health problems and increasing research efforts are required to understand the molecular mechanisms underlying kidney injury to identify new therapeutic approaches.Gremlin is a highly conserved secreted protein that is present both on the external cell surface and within the ER-Golgi compartment of different cell types [1,2], affecting diverse biological processes such as growth, differentiation and development [2]
In biopsies obtained from patients with diabetic nephropathy, we have observed gremlin expression in areas with tubule-interstitial fibrosis, and it colocalizes with transforming growth factor-b (TGF-b) [9]
We found that GREM1-expressing mice presented normal renal function, but they were more susceptible to developing renal damage induced by folic acid (FA) administration, suggesting that gremlin plays a pathogenic role in renal damage
Summary
Kidney disease and renal failure are worldwide health problems and increasing research efforts are required to understand the molecular mechanisms underlying kidney injury to identify new therapeutic approaches.Gremlin is a highly conserved secreted protein that is present both on the external cell surface and within the ER-Golgi compartment of different cell types [1,2], affecting diverse biological processes such as growth, differentiation and development [2]. The Grem1-null mouse was the first in vivo gremlin model This model was neonatally lethal, and the embryos presented kidney and lung defects [4]. The gremlin gene may be induced in human mesangial cell cultures that are exposed to high glucose levels and is expressed in the kidneys of diabetic rats [6,7,8]. In biopsies obtained from patients with diabetic nephropathy, we have observed gremlin expression in areas with tubule-interstitial fibrosis, and it colocalizes with transforming growth factor-b (TGF-b) [9]. Gremlin is expressed in cellular glomerular crescents and in the tubular and infiltrating interstitial cells of human biopsies of pauci-immune glomerulonephritis and chronic allograft nephropathy, broadening the range of activity to a more global role for gremlin in renal diseases [10,11]. There are no data regarding the direct effect of gremlin in the kidney
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
