title: Daily exercise training protects against albuminuria and angiotensin converting enzyme 2 shedding in db/db diabetic mice.
abstract: Angiotensin II (Ang II) is involved in induction and progression of renal damage in diabetes. Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and has been shown to be renoprotective by degrading Ang II to Ang-(1-7). A disintegrin and metalloproteinase 17 (ADAM17)-mediated shedding of renal ACE2 contribute to diabetic nephropathy pathogenesis. Lifestyle modification and metformin are recommended as initial therapies for most patients with type 2 diabetes. The aim of this study was to investigate whether exercise training and/or metformin improve glucose homeostasis and albuminuria and downregulate renal ADAM17 and ACE2 shedding in db/db mice. Seven-week-old normal and db/db mice were subjected either to a sedentary existence or exercise training with and without metformin (150 mg/kg per day) for 10 weeks. Exercise training significantly lowered blood glucose, urinary albumin and ACE2 excretion in db/db mice. ADAM17 and ACE2 proteins were co-localized in cortical tubules of the kidney, indicating a possible interaction. Metformin treatment was effective in lowering hyperglycemia only during the first 2 weeks of treatment. Increased renal ADAM17 in 17-week-old db/db mice was corrected by physical exercise but not metformin. In addition, exercise training reduced plasma triglycerides and enhanced insulin levels of db/db mice. In conclusion, exercise training alone and in combination with metformin prevented shedding of renal ACE2 by decreasing ADAM17 protein. Urinary ACE2 could serve as a prognostic tool for the progression of kidney damage and its attenuation by exercise may partially contribute to its renal protection.
authors.affiliation: Departments of Pharmacology and Toxicology Pathology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435, USA Veterans Affairs Medical Center, Cincinnati, Ohio 45220, USA.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Somineni
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Boivin
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Elased
mesh_terms: D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D003131:Combined Modality Therapy; D048909:Diabetes Complications / Q000517:prevention & control / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000628:therapy* / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000628:therapy / Q000652:urine; D005081:Exercise Therapy / Q000379:methods*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007668:Kidney / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000652:urine*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D021381:Protein Transport; D054411:Receptors, Leptin / Q000235:genetics
chemical_list: D007004:Hypoglycemic Agents; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D008687:Metformin; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: ADAM17; diabetic nephropathy; exercise; metformin; type 2 diabetes; urinary ACE2
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