title: Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice.
abstract: Diabetic nephropathy, the leading cause of end-stage renal disease, is characterized by a proapoptotic and prooxidative environment. The mechanisms by which lifestyle interventions, such as exercise, benefit diabetic nephropathy are unknown. We hypothesized that exercise inhibits early diabetic nephropathy via attenuation of the mitochondrial apoptotic pathway and oxidative damage. Type 2 diabetic db/db and normoglycemic wild-type mice were exercised for an hour everyday at a moderate intensity for 7 wk, following which renal function, morphology, apoptotic signaling, and oxidative stress were evaluated. Exercise reduced body weight, albuminuria, and pathological glomerular expansion in db/db mice independent of hyperglycemic status. Changes in renal morphology were also related to reduced caspase-3 (main effector caspase in renal apoptosis), caspase-8 (main initiator caspase of the "extrinsic" pathway) activities, and TNF-alpha expression. A role for the mitochondrial apoptotic pathway was unlikely as both caspase-9 activity (initiator caspase of this pathway) and expression of regulatory proteins such as Bax and Bcl-2 were unchanged. Kidneys from db/db mice also produced higher levels of superoxides and had greater oxidative damage concurrent with downregulation of superoxide dismutase (SOD) 1 and 3. Interestingly, although exercise also increased superoxides, there was also upregulation of multiple SODs that likely inhibited lipid (hydroperoxides) and protein (carbonyls and nitrotyrosine) oxidation in db/db kidneys. In conclusion, exercise can inhibit progression of early diabetic nephropathy independent of hyperglycemia. Reductions in caspase-3 and caspase-8 activities, with parallel improvements in SOD expression and reduced oxidative damage, could underlie the beneficial effects of exercise in diabetic kidney disease.
authors.affiliation: Dept. of Anaesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, Univ. of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors.forename: S
authors.initials: S
authors.lastname: Ghosh
authors.forename: M
authors.initials: M
authors.lastname: Khazaei
authors.forename: F
authors.initials: F
authors.lastname: Moien-Afshari
authors.forename: L S
authors.initials: LS
authors.lastname: Ang
authors.forename: D J
authors.initials: DJ
authors.lastname: Granville
authors.forename: C B
authors.initials: CB
authors.lastname: Verchere
authors.forename: S R
authors.initials: SR
authors.lastname: Dunn
authors.forename: P
authors.initials: P
authors.lastname: McCue
authors.forename: A
authors.initials: A
authors.lastname: Mizisin
authors.forename: K
authors.initials: K
authors.lastname: Sharma
authors.forename: I
authors.initials: I
authors.lastname: Laher
mesh_terms: D000367:Age Factors; D000419:Albuminuria / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D005081:Exercise Therapy; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D013482:Superoxide Dismutase; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8