Abstract
Exercise training is known to exert multiple beneficial effects including renal protection in type 2 diabetes mellitus and obesity. However, the mechanisms regulating these actions remain unclear. The present study evaluated the effects of chronic running exercise on the early stage of diabetic nephropathy, focusing on nitric oxide synthase (NOS), oxidative stress and glycation in the kidneys of Zucker diabetic fatty (ZDF) rats. Male ZDF rats (6 weeks old) underwent forced treadmill exercise for 8 weeks (Ex-ZDF). Sedentary ZDF (Sed-ZDF) and Zucker lean (Sed-ZL) rats served as controls. Exercise attenuated hyperglycemia (plasma glucose; 242 ± 43 mg/dL in Sed-ZDF and 115 ± 5 mg/dL in Ex-ZDF) with increased insulin secretion (plasma insulin; 2.3 ± 0.7 and 5.3 ± 0.9 ng/mL), reduced albumin excretion (urine albumin; 492 ± 70 and 176 ± 11 mg/g creatinine) and normalized creatinine clearance (9.7 ± 1.4 and 4.5 ± 0.8 mL/min per body weight) in ZDF rats. Endothelial (e) and neuronal (n) NOS expression in kidneys of Sed-ZDF rats were lower compared with Sed-ZL rats (p<0.01), while both eNOS and nNOS expression were upregulated by exercise (p<0.01). Furthermore, exercise decreased NADPH oxidase activity, p47phox expression (p<0.01) and α-oxoaldehydes (the precursors for advanced glycation end products) (p<0.01) in the kidneys of ZDF rats. Additionally, morphometric evidence indicated renal damage was reduced in response to exercise. These data suggest that upregulation of NOS expression, suppression of NADPH oxidase and α-oxoaldehydes in the kidneys may, at least in part, contribute to the renal protective effects of exercise in the early progression of diabetic nephropathy in ZDF rats. Moreover, this study supports the theory that chronic aerobic exercise could be recommended as an effective non-pharmacological therapy for renoprotection in the early stages of type 2 diabetes mellitus and obesity.
Highlights
Sedentary behavior is known to increase obesity, aggravate type 2 diabetes mellitus (T2DM) and lead to early mortality [1]
Total cholesterol, triglycerides, free fatty acids and blood urea nitrogen were significantly higher in the Sed-Zucker diabetic fatty (ZDF) group than those in the Sed-ZL group, and plasma creatinine level was significantly lower in the Sedentary ZDF (Sed-ZDF) than the Sed-ZL group (p
There was no significant difference in uric acid between the groups, the albumin-to-creatinine ratio and the creatinine clearance-to-bodyweight ratio were significantly higher in the Sed-ZDF group compared with the Sed-ZL group, whereas the ratios were significantly lower in the Ex-ZDF group compared with the Sed-ZDF group
Summary
Sedentary behavior is known to increase obesity, aggravate type 2 diabetes mellitus (T2DM) and lead to early mortality [1]. Several studies have shown that exercise can be beneficial for diabetic nephropathy in obese Zucker rats [3, 4] and type 1 diabetic rats [5]. Exercise can prevent insulin secretion failure through increased β-cell function and mass [6, 7], and decreased hepatic inflammation and oxidative stress [8] in Zucker diabetic fatty (ZDF) rats. These studies have largely focused on the pancreas and liver for potential mechanisms of exercise treatment in ZDF rats. The effects of exercise on kidney-related mechanisms in ZDF rats are unknown
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