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      Chronic Running Exercise Alleviates Early Progression of Nephropathy with Upregulation of Nitric Oxide Synthases and Suppression of Glycation in Zucker Diabetic Rats

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          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, p47 phox 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.

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          Most cited references 34

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          Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes.

          Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes. More than half of the new patients admitted to dialysis therapy in some centers are diagnosed with type IIb diabetes, that is, diabetes associated with obesity. This study searched for a common final pathway of renal damage in this progressive renal disease. The evolution of biochemical and morphological renal changes was examined in 6- to 60-week-old Zucker rats (fa/fa-rats), a model of obesity associated with type II diabetes. fa/fa-rats exhibited pronounced hyperinsulinemia and hyperlipidemia at 6 weeks and became diabetic after 14 weeks of age. Significant focal segmental glomerulosclerosis was first noted in 18-week-old fa/fa-rats and tubulointerstitial damage and proteinuria in 40-week-old fa/fa-rats. A comparison of kidneys of six-week-old fa/fa-and lean control (Fa/?) rats by immunohistology revealed a 1.8-fold increase in glomerular monocyte/macrophage counts in fa/fa-rats and a significant increase in de novo desmin expression in podocytes. Electron microscopy demonstrated an increase in the number of podocyte mitochondria and intracytoplasmic protein and fat droplets. Podocyte desmin scores markedly increased until week 18 in fa/fa-rats, whereas glomerular monocyte/macrophage counts peaked at 3.2-fold at week 14. Podocyte desmin expression, but not glomerular macrophage infiltration, correlated with damage in adjacent tubular cells, as evidenced by their de novo expression of vimentin. Progressive glomerular hypertrophy was detected in fa/fa-rats after 10 weeks. GBM width was significantly increased in 14-week-old fa/fa-rats as compared with lean controls. Mesangial cell activation (de novo expression of alpha-smooth muscle actin) and proliferation was low to absent throughout the observation period in fa/fa-rats. Renal cell death counts (TUNEL) remained unchanged in 6- to 40-week-old fa/fa-rats. Tubulointerstitial myofibroblast formation and matrix accumulation occurred late during the study duration in fa/fa-rats. These data suggest that early progressive podocyte damage and macrophage infiltration is associated with hyperlipidemia and type IIb diabetes mellitus, and antedates both the development of glomerulosclerosis and tubulointerstitial damage.
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            Oxidative stress in early diabetic nephropathy: fueling the fire.

            Diabetic nephropathy is a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease worldwide. The treatment costs of diabetes mellitus and its complications represent a huge burden on health-care expenditures, creating a major need to identify modifiable factors concerned in the pathogenesis and progression of diabetic nephropathy. Chronic hyperglycemia remains the primary cause of the metabolic, biochemical and vascular abnormalities in diabetic nephropathy. Promotion of excessive oxidative stress in the vascular and cellular milieu results in endothelial cell dysfunction, which is one of the earliest and most pivotal metabolic consequences of chronic hyperglycemia. These derangements are caused by excessive production of advanced glycation end products and free radicals and by the subjugation of antioxidants and antioxidant mechanisms. An increased understanding of the role of oxidative stress in diabetic nephropathy has lead to the exploration of a number of therapeutic strategies, the success of which has so far been limited. However, judicious and timely use of current therapies to maintain good glycemic control, adequate blood pressure and lipid levels, along with lifestyle measures such as regular exercise, optimization of diet and smoking cessation, may help to reduce oxidative stress and endothelial cell dysfunction and retard the progression of diabetic nephropathy until more definitive therapies become available.
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              Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage.

              Tonic basal release of nitric oxide (NO) by vascular endothelial cells controls blood pressure (BP) in the basal state. In these studies we investigated the effects of chronic inhibition of basal NO synthesis in the rat for a 2-mo period. Significant systemic hypertension developed in chronically NO-blocked rats compared to controls. Marked renal vasoconstriction was also observed with elevations in glomerular blood pressure (PGC) and reductions in the glomerular capillary ultrafiltration coefficient (Kf). Chronically NO-blocked rats also develop proteinuria and glomerular sclerotic injury compared to controls. These studies therefore describe a new model of systemic hypertension with glomerular capillary hypertension and renal disease due to chronic blockade of endogenous NO synthesis. These observations highlight the importance of the endogenous NO system in control of normal vascular tone and suggest that hypertensive states may result from relative NO deficiency.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 September 2015
                2015
                : 10
                : 9
                Affiliations
                [1 ]Department of Miyagi Community Health Promotion, Tohoku University Graduate School of Medicine, Tohoku University, Sendai, Japan
                [2 ]Department of Internal Medicine and Rehabilitation Science, Tohoku University Graduate School of Medicine, Tohoku University, Sendai, Japan
                [3 ]Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences and Medicine, Tohoku University, Sendai, Japan
                [4 ]Department of Integrated Nephrology and Telemedicine, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
                University of Louisville, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: DI. Performed the experiments: DI PC TK ES CS GH YO. Analyzed the data: DI PC ES CS YM. Contributed reagents/materials/analysis tools: ES TI OI MK HK. Wrote the paper: DI.

                Article
                PONE-D-15-21862
                10.1371/journal.pone.0138037
                4574951
                26379244

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 9, Tables: 1, Pages: 21
                Product
                Funding
                This work was supported by a grant to DI from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (23700593). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                Research Article
                Custom metadata
                All relevant data are within the paper.

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