The Story of Notch in the Kidney: Development and Disease

Diabetic nephropathy is currently the leading cause of end-stage renal disease worldwide, and occurs in approximately one third of all diabetic patients. The molecular pathogenesis of diabetic nephropathy has not been fully characterized and novel mediators and drivers of the disease are still being described. Previous data from our laboratory has identified the developmentally regulated gene Gremlin as a novel target implicated indiabetic nephropathy in vitro and in vivo. Notch signalling is a highly conserved cell–cell communication mechanism that regulates development, tissuehomeostasis, and repair. Within the kidney, Notch has an important function in orchestrating kidney development. Recent studies indicate that Notch plays a key role in establishing proximal epithelial fate during nephronsegmentation as well as the differentiation of principal cells in the renal collecting system. Notch signalling ismarkedly reduced in the adult kidney; however, increased Notch signalling has been noted in both acute andchronic kidney injury. Increased glomerular epithelial Notch signalling has been associated with albuminuria and glomerulosclerosis, while tubular epithelial Notch activation caused fibrosis development most likely inducingan improper epithelial repair pathway. Recent studies thereby indicate that Notch is a key regulator of kidney development, repair, and injury. Angiotensin II (AngII) plays a key role in the progression of kidney diseases. A ngII contributes to renal fibrosis by upregulation of profibrotic factors, induction of epithelial mesenchymal transition and accumulation of extracellular matrix proteins. Incultured human tubular epithelial cells, the Notch activation by transforming growth factor-b1 (TGF-b1) has been involved inepithelial mesenchymal transition. AngII mimics many profibrotic actions of TGF-b1.