Abstract
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-β 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.
Highlights
Diabetic kidney disease (DKD) is the principal cause of renal failure worldwide
Both angiotensin-converting enzyme (ACE) inhibitors and angiotensinII receptor blockers (ARB) are known to reduce blood pressure and to increase plasma renin activity, while chymase inhibitors do not affect blood pressure and plasma renin activity [6]. These findings suggest that chymase inhibitors, but not ACE inhibitors and ARBs, are uninvolved in the regulation of systemic angiotensin II levels
Angiotensin II plays a crucial role in podocyte injury; high glucose increases angiotensin II formation in cultured mouse podocytes, and its increase can be inhibited by a chymase
Summary
Diabetic kidney disease (DKD) is the principal cause of renal failure worldwide. Angiotensin II promotes the progression of DKD, and angiotensin-converting enzyme (ACE) inhibitors and angiotensin. Sci. 2020, 21, 7495; doi:10.3390/ijms21207495 www.mdpi.com/journal/ijms increase in glomerular chymase expression is observed in patients with diabetic nephropathy [10] These reports suggest that chymase-dependent angiotensin II formation may play an important role in the pathogenesis of DKD, especially podocyte injury. An augmentation of TGF-β gene expression is observed along with progressive podocyte injury in mice [13]. Both angiotensin II and high glucose induce TGF-β gene inhibitor but by anresulting. The db/db mouse is a genetic obese diabetic model that develops abnormalities in renal function progressive podocyte injury in those mice [13]. 51469-treated groups continued until 4 weeks after starting treatment, and no significant difference between placebo- and TY-51469-treated groups was observed (Figure 1a)
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