The involvement of the Notch signaling pathway in the cellular differentiation of the mammalian kidney is established. Recently, the dysregulation of Notch signaling molecules has been identified in acute and chronic renal injuries, fibrosis models, and diabetic kidney biopsies. The canonical Notch ligand , Jagged1, is upregulated in a transforming growth factor-beta- (TGF-β-) dependent manner during chronic kidney disease. TGF-β, a central mediator of renal fibrosis, also is a major contributor to the development of diabetic nephropathy. To explore the roles and possible mechanisms of Notch signaling molecules in the pathogenesis of diabetic nephropathy, we exposed cultured rat mesangial cells to a γ-secretase inhibitor (DAPT) or high glucose and measured the expression of Notch signaling molecules and the fibrosis index. Notch pathway-related molecules, TGF-β, and fibronectin increased with exposure to high glucose and decreased with DAPT treatment. Our results suggest that the Notch signaling pathway may precipitate diabetic nephropathy via TGF-β activation. 1. Introduction Diabetic nephropathy is a common microvascular complication of diabetes with a poorly understood pathogenesis. Hemodynamic changes and disorders of glucose metabolism resulting from genetic factors, hyperglycemia, and/or the actions of angiotensin II and other cytokines can precipitate in the development of diabetic nephropathy. Notably, activation of the Notch signaling pathway can induce the formation of glomerular and tubular lesions that are characteristic of this disease [1, 2]. The Notch ligand, Jagged1, and its target gene product, Hes1, are elevated in renal biopsies from diabetic nephropathy patients, further implicating Notch activation in this disease [3–5]. Despite evidence that Notch activation is present in diabetic nephropathy specimens in vivo, no reports have investigated Notch signaling during the development of diabetic nephropathy. The early stages of diabetic nephropathy are associated with changes in certain cytokines, growth factors, and adhesion molecules, including TGF- , a central mediator of the fibrotic response. Enhanced fibronectin (FN) deposition ultimately leads to glomerulosclerosis and tubulointerstitial fibrosis, which are characteristics of end-stage diabetic nephropathy [6]. The levels of Jagged1, Jagged2, and Notch1, 4 were upregulated significantly in a human kidney epithelial cell line (CC-2554) with TGF- treatment in a dose-dependent manner [7]. Whether the Notch signaling pathway is involved directly in the pathogenesis of diabetic
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