Mechanism of Albuminuria Reduction by Chymase Inhibition in Diabetic Mice.

Chymase has several functions, such as angiotensin II formation, which can promote diabetic kidney disease (DKD). In this study, we evaluated the effect of the chymase inhibitor TY-51469 on DKD in diabetic db/db mice. Diabetic mice were administered TY-51469 (10 mg/kg/day) or placebo for 4 weeks. No significant difference was observed in body weight and fasting blood glucose between TY-51469- and placebo-treated groups. However, a significant reduction in urinary albumin/creatinine ratio was observed in the TY-51469-treated group compared with the placebo-treated group. In the renal extract, chymase activity was significantly higher in placebo-treated mice than in non-diabetic db/m mice, but it was reduced by treatment with TY-51469. Both NADPH oxidase 4 expression and the oxidative stress marker malondialdehyde were significantly augmented in the placebo-treated group, but they were attenuated in the TY-51469-treated group. Significant increases of tumor necrosis factor-α and transforming growth factor-ß mRNA levels in the placebo-treated group were significantly reduced by treatment with TY-51469. Furthermore, the expression of nephrin, which is a podocyte-specific protein, was significantly reduced in the placebo-treated group, but it was restored in the TY-51469-treated group. These findings demonstrated that chymase inhibition reduced albuminuria via attenuation of podocyte injury by oxidative stress.

Possible Roles of Periostin in the Formation of Hemodialysis Vascular Access Stenosis after Polytetrafluoroethylene Graft Implantation in Dogs.

Periostin, a recently found matricellular protein, has been implicated in neointima formation after balloon injury. However, the relationship between periostin and hyperplastic intima formation after PTFE graft implantation is unclear. Under mixed anesthesia, PTFE grafts were implanted between the canine carotid artery and jugular vein, and PTFE graft samples were harvested 1, 2, and 4 months after implantation. Intima formation started on the luminal surface of PTFE grafts at the venous anastomotic region 1 month after implantation. Thereafter, the increase in intimal volume was not only observed in the venous and arterial anastomotic regions, but also in the middle region of the PTFE grafts. In accordance with the increased intimal formation, time-dependent increases in mRNA expressions of periostin and transforming growth factor beta 1 (TGF-ß1), as well as a strong positive correlation between periostin and TGF-ß1, were observed. These findings suggest that periostin may play a very important role in the pathogenesis of hemodialysis vascular access stenosis through the acceleration of intimal formation. Thus, periostin may be a very important therapeutic target for the treatment of vascular access graft dysfunction in hemodialysis patients.