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.

Gremlin1 plays a key role in kidney development and renal fibrosis

“…13). Previous reports demonstrated that tubular epithelial overexpression of Grem via a kidney androgen-regulated promoter aggravated renal damage in FA injury and DN after 25 wk (9, 17). The exact signaling modalities of Grem1 in the diseased kidney are not clear.…”

“…Grem1 levels are increased in diabetic nephropathy (DN), chronic allograft nephropathy, immune glomerulonephritis, and acute kidney injury (AKI) (2, 9, 17, 18, 33). Higher levels of Grem1 expression in the kidney correlate with indexes of renal damage (8, 33).…”

“…Higher levels of Grem1 expression in the kidney correlate with indexes of renal damage (8, 33). In the context of renal fibrosis, tubular epithelial overexpression of Grem1 in mouse models of AKI and DN resulted in increased renal damage and a more severe phenotype (9, 17). Consistently, Grem1 targeting has shown potential benefits, with both allelic depletion and siRNA targeting of Grem1 protecting against the early sequelae of DN (28, 35).…”

Molecular mechanism of smurf2 in regulating the expression of SnoN in diabetic nephropathy

“…DN is one of the most important microvascular complication of diabetes and is the leading cause of end-stage kidney failure worldwide, contributing to morbidity and mortality rates (14). Due to the complexity of metabolic disorders, the treatment of DN is more difficult, compared with other kidney diseases.…”

Kidney atrophy vs hypertrophy in diabetes: which cells are involved?

“…In addition, tubular and interstitial lesions are prominent in diabetic patients. An increase in tubular basement membrane thickening that accompanies the development of renal hypertrophy is considered one of the earliest renal pathological changes in diabetes [6][7][8]. The changes in the tubular occur are independent on the pathological changes that associated with progressive of diabetic nephropathy and strongly correlated with glycemic control.…”