Recapitulation of Embryological Programmes in Renal Fibrosis – The Importance of Epithelial Cell Plasticity and Developmental Genes

Abstract

Chronic fibrosis represents the final common pathway in progressive renal disease. Myofibroblasts deposit the constituents of renal scar, thus crippling renal function. It has recently emerged that an important source of these pivotal effector cells is the injured renal epithelium. This review concentrates on the process of epithelial-mesenchymal transition (EMT) and its regulation. The role of the developmental gene, gremlin, which is reactivated in adult renal disease, is the subject of particular focus. This member of the cysteine knot protein superfamily is critical to the process of nephrogenesis but quiescent in normal adult kidney. There is increasing evidence that gremlin expression reactivates in diabetic nephropathy, and in the diseased fibrotic kidney per se. Known to antagonize members of the bone morphogenic protein (BMP) family, gremlin may also act downstream of TGF-β in induction of EMT. An increased understanding of the extracellular modulation of EMT and, in particular, of the gremlin-BMP axis may result in strategies that can halt or reverse the devastating progression of chronic renal fibrosis.

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

“…Accordingly, in TG/STZ mice TGF-␤1 and Gremlin expression was significantly higher than in WT/STZ mice. Previous studies in cultured renal cells, including mesangial cells, podocytes, fibroblasts, and tubuloepithelial cells, have described that Gremlin regulates other profibrotic factors, including connective tissue growth factor (CTGF) (36,38) and fibroblast growth factor (FGF) (19), increases the production of extracellular matrix proteins, and induces tubuloepithelial-to-mesenchymal transition (6,36,37). The analysis of specific fibrotic markers in Gremlin TG/STZ mice showed significant inductions of the extracellular matrix components (ECM) fibronectin and collagen type 1, as well ␣-SMA, a marker of fibrotic phenotype and activated fibroblasts.…”

Regulation and consequences of differential gene expression in diabetic kidney disease

“…Gremlin has been reported to influence diverse processes in growth, differentiation and development [13,15]. Gremlin expression was increased by both cyclic mechanical strain in vitro, a model of the glomerular hypertension associated with DN, and in the kidneys isolated from rats with STZ-induced diabetes in vivo [14].…”

Reactivation ofSnailGenes in Renal Fibrosis and Carcinomas: A Process of Reversed Embryogenesis?

“…14 In addition, BMP7 also plays an important role in the modulation of MET. 15,16 BMP7 is secreted by the bud tip cells and the condensed mesenchyme 17 but not by the metanephric undifferentiated mesenchyme where Snail genes are specifically expressed. This suggests that BMP7 may participate in the downregulation of Snail genes concomitant with renal mesenchyme differentiation.…”