Therapeutic effect of alprostadil in diabetic nephropathy: possible roles of angiopoietin-2 and IL-18.

BACKGROUND/AIMS: To investigate the role of angiopoietin-2 (Ang-2) and IL-18 in the pathogenesis of diabetic nephropathy (DN) and the molecular mechanisms through which alprostadil protects renal function. METHODS: DN was induced by streptozotocin and intraperitoneal injection of alprostadil was given to diabetic mice. After 2, 4 and 8 weeks of alprostadil treatment, the mRNA and protein expression of kidney Ang-2 and IL-18 were detected by reverse transcription PCR, Western blot and immunohistochemistry analyses. Mouse glomerular endothelial cells (GEnCs) were cultured in high glucose and treated with alprostadil. After transfection with an Ang-2-pcDNA and Ang-2-siRNA, both Ang-2 and IL-18 expression were measured by Western blot analyses. RESULTS: Alprostadil treatment caused a significant decrease in the renal damage parameters. Both Ang-2 and IL-18 were significantly increased in DN mice and in GEnCs cultured in high glucose; however, their expression was greatly reduced by alprostadil treatment. Ang-2 could also increase IL-18 expression in cultured endothelial cells under high glucose, and this response was partially blocked by Ang-2 siRNA. CONCLUSIONS: Ang-2 and IL-18 may be associated with the development and progression of DN in mice. Alprostadil treatment can protect renal function by reducing proteinuria. These effects are mediated, at least in part, through down-regulation of Ang-2 and IL-18 expression.