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Pan-Nox inhibitor treatment improves renal function in aging murine diabetic kidneys
Jeong Hoon Park1, Sung Gi Yoon1, Jung Yeon Ghee1
1Division of Nephrology, Department of Internal Medicine, Korea University College of Medicine, Republic of Korea.
Background:
Aging is a risk factor for development of chronic kidney disease and diabetes mellitus with commonly shared features of chronic inflammation and increased oxidative stress. Here, we investigated the effect of pan-Nox-inhibitor, APX-115, on renal function in aging diabetic mice.
Methods:
Diabetes was induced by intraperitoneal injection of streptozotocin at 50 mg/kg/day for 5 days in 52-week-old C57BL/6J mice. APX-115 was administered by oral gavage at a dose of 60 mg/kg/day for 12 weeks in nondiabetic and diabetic aging mice.
Results:
APX-115 significantly improved insulin resistance in diabetic aging mice. Urinary level of 8-isoprostane was significantly increased in diabetic aging mice than nondiabetic aging mice, and APX-115 treatment reduced 8-isoprostane level. Urinary albumin and nephrin excretion were significantly higher in diabetic aging mice than nondiabetic aging mice. Although APX-115 did not significantly decrease albuminuria, APX-115 markedly improved mesangial expansion, macrophage infiltration, and expression of fibrosis molecules such as transforming growth factor beta 1 and plasminogen activator inhibitor 1. Interestingly, the expression of all Nox isoforms including Nox1, Nox2, and Nox4 was significantly increased in diabetic aging kidneys, and APX-115 treatment decreased Nox1, Nox2, and Nox4 protein expression in the kidney. Furthermore, Klotho expression was significantly decreased in diabetic aging kidneys, and APX-115 restored Klotho level.
Conclusion:
Our results provide evidence that pan-Nox inhibition may improve systemic insulin resistance and decrease oxidative stress, inflammation, and fibrosis in aging diabetic status and may have potential protective effects on aging diabetic kidney.
Insights
Pan-Nox inhibitor APX-115 improved insulin resistance and reduced oxidative stress and fibrosis in aging diabetic mice. This suggests APX-115 may protect aging diabetic kidneys by targeting Nox isoforms and restoring Klotho levels.
Area of Science:
- Nephrology
- Gerontology
- Pharmacology
Background:
- Aging is a significant risk factor for chronic kidney disease (CKD) and diabetes mellitus.
- Both aging and diabetes share common pathological features including chronic inflammation and oxidative stress.
- The role of NADPH oxidase (Nox) enzymes in aging and diabetic kidney disease warrants further investigation.
Purpose of the Study:
- To investigate the therapeutic effect of a pan-Nox inhibitor, APX-115, on renal function in aging diabetic mice.
- To assess the impact of APX-115 on oxidative stress, inflammation, fibrosis, and insulin resistance in this model.
Main Methods:
- Diabetes was induced in 52-week-old C57BL/6J mice using streptozotocin.
- APX-115 was administered orally for 12 weeks to both nondiabetic and diabetic aging mice.
- Renal function, oxidative stress markers (8-isoprostane), albuminuria, nephrin excretion, kidney histology, Nox isoform expression, and Klotho levels were analyzed.
Main Results:
- APX-115 significantly improved insulin resistance and reduced urinary 8-isoprostane levels in diabetic aging mice.
- Treatment with APX-115 improved kidney histology by reducing mesangial expansion and macrophage infiltration, and decreased expression of fibrosis markers.
- APX-115 decreased the expression of Nox1, Nox2, and Nox4 isoforms in the kidneys and restored decreased Klotho levels.
Conclusions:
- Pan-Nox inhibition with APX-115 demonstrates potential protective effects on aging diabetic kidneys.
- APX-115 may improve systemic insulin resistance and mitigate oxidative stress, inflammation, and fibrosis in aging diabetic conditions.
- Targeting Nox enzymes represents a promising therapeutic strategy for managing complications in aging diabetic kidney disease.
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