Abstract
Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse) and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1) is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.
Highlights
The worldwide prevalence of diabetes in all age groups was 2.8% in 2000 and is estimated to be 4.4% in 2030 [1]
The urinary albumin excretions were significantly increased in untreated Akita mice compared to wild-type controls, and administration of telmisartan significantly reduced urinary albumin excretion (Table 1)
We investigated the activation of the Notch pathway in the glomeruli of Akita mice
Summary
The worldwide prevalence of diabetes in all age groups was 2.8% in 2000 and is estimated to be 4.4% in 2030 [1]. The total number of people with diabetes mellitus (DM) is expected to rise from 171 million in 2000 to 366 million in 2030. A major microvascular complication of DM, is the most common cause of end-stage renal disease (ESRD) [2]. A number of pathways such as the protein kinase C pathway [3] and the polyol pathway [4] as well as advanced glycation end products [5] have been reported to play important roles in the development of diabetic nephropathy. It has been reported that the renin-angiotensin system (RAS) plays a potent role in the initiation and progression of diabetic nephropathy [6]
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