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.

Tnf-α inhibition by infliximab as a new target for the prevention of glycerol-contrast-induced nephropathy

“…In studies seeking to identify the tubular epithelial injury, tubular necrosis, hyaline casts, and haemorrhagic casts were investigated (Droguett et al, 2014). With developing nephropathy, significant damage in haemorrhagic renal tubules, with hyaline, occurs and is related to tubular injury.…”

Tubular overexpression of Gremlin in transgenic mice aggravates renal damage in diabetic nephropathy

“…Therefore, all of these data suggest that Gremlin could contribute to tubulointerstitial fibrosis by direct activation of tubulointerstitial cells. Recently, our group generated a transgenic (TG) mouse expressing human Gremlin specifically in renal proximal tubular cells under the control of an androgen-regulated promoter (11). This tubular Gremlin overexpression generates no functional abnormalities or renal damage under physiological conditions, but exerts increased susceptibility to folic acid-induced acute renal injury (11).…”

“…Recently, our group generated a transgenic (TG) mouse expressing human Gremlin specifically in renal proximal tubular cells under the control of an androgen-regulated promoter (11). This tubular Gremlin overexpression generates no functional abnormalities or renal damage under physiological conditions, but exerts increased susceptibility to folic acid-induced acute renal injury (11). In diabetic nephropathy, besides podocyte damage, the progression to end-stage renal failure is related to tubulointerstitial fibrosis.…”

A novel approach to contrast-induced nephrotoxicity: the melatonergic agent agomelatine

“…54 In the development of nephropathy, significant damage to haemorrhagic renal tubules with hyaline occurs and is related to tubular injury. We determined positive effects of agomelatine administration on tubular structure.…”