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Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters
Yasutaka Maeda1, Toyoshi Inoguchi, Ryoko Takei
1Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Insights
Chymase inhibition effectively treats diabetic nephropathy by reducing intrarenal angiotensin II and oxidative stress. This novel approach targets chymase, offering a promising therapeutic strategy for kidney disease in diabetes.
Area of Science:
- Nephrology
- Endocrinology
- Biochemistry
Background:
- The intrarenal renin-angiotensin system is implicated in diabetic nephropathy progression.
- Chymase, a local angiotensin II-forming enzyme, has an unclear role in this condition.
Purpose of the Study:
- To investigate the causal role of chymase in diabetic nephropathy.
- To evaluate the therapeutic effectiveness of chymase inhibition.
Main Methods:
- Streptozotocin-induced diabetic hamster model.
- Oral administration of chymase inhibitor TEI-F00806.
- Assessment of proteinuria, glomerular TGF-β, fibronectin, mesangial expansion, intrarenal angiotensin II, oxidative stress, and NAD(P)H oxidase components.
Main Results:
- Renal chymase expression was significantly upregulated in diabetic hamsters.
- TEI-F00806 ameliorated proteinuria, fibrosis markers, and mesangial expansion by normalizing intrarenal angiotensin II.
- Chymase inhibition improved oxidative stress and NAD(P)H oxidase components, independent of blood pressure.
- Ramipril showed less efficacy compared to TEI-F00806.
Conclusions:
- Chymase plays a causal role in diabetic nephropathy.
- Chymase inhibition is a potential therapeutic strategy for diabetic nephropathy.
- Targeting chymase may protect against intrarenal angiotensin II elevation, oxidative stress, and renal dysfunction in diabetes.
Abstract:
Accumulating evidence suggests that the intrarenal renin-angiotensin system may be involved in the progression of diabetic nephropathy. Chymase is a potent local angiotensin II-forming enzyme in several species, including humans and hamsters. However, the pathophysiological role of chymase is not fully understood. Here, we report a causal role of chymase in diabetic nephropathy and the therapeutic effectiveness of chymase inhibition. In the present study, renal chymase expression was markedly upregulated in streptozotocin-induced diabetic hamsters. Oral administration of a specific chymase inhibitor, TEI-F00806, completely ameliorated proteinuria, the overexpression of transforming growth factor-β and fibronectin in glomeruli, and renal mesangial expansion, by normalizing the increase in intrarenal angiotensin II levels in diabetic hamsters independently of blood pressure levels. In contrast, ramipril did not show such sufficient effects. These effects occurred in parallel with improvements in superoxide production and expression of NAD(P)H oxidase components [NAD(P)H oxidase 4 and p22(phox)] in glomeruli. This study showed for the first time that chymase inhibition may protect against elevated intrarenal angiotensin II levels, oxidative stress, and renal dysfunction in diabetes. These findings suggest that chymase offers a new therapeutic target for diabetic nephropathy.
