Document Detail


Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice.
MedLine Citation:
PMID:  19144689     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
S Ghosh; M Khazaei; F Moien-Afshari; L S Ang; D J Granville; C B Verchere; S R Dunn; P McCue; A Mizisin; K Sharma; I Laher
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-01-14
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  296     ISSN:  1931-857X     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-03-23     Completed Date:  2009-06-02     Revised Date:  2011-04-28    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F700-8     Citation Subset:  IM    
Affiliation:
Dept. of Anaesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, Univ. of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
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MeSH Terms
Descriptor/Qualifier:
Age Factors
Albuminuria / enzymology,  etiology,  pathology,  prevention & control*
Animals
Apoptosis*
Caspase 3 / metabolism*
Caspase 8 / metabolism
Diabetes Mellitus, Type 2 / complications,  enzymology,  pathology,  therapy*
Diabetic Nephropathies / enzymology,  etiology,  pathology,  prevention & control*
Disease Models, Animal
Disease Progression
Down-Regulation
Exercise Therapy*
Kidney / enzymology*,  pathology
Male
Mice
Mitochondria / enzymology,  pathology
Oxidative Stress*
Proto-Oncogene Proteins c-bcl-2 / metabolism
Superoxide Dismutase / metabolism
Tumor Necrosis Factor-alpha / metabolism
bcl-2-Associated X Protein / metabolism
Grant Support
ID/Acronym/Agency:
R01-DK-53867/DK/NIDDK NIH HHS; U01-DK-076133/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Bax protein, rat; 0/Proto-Oncogene Proteins c-bcl-2; 0/Tumor Necrosis Factor-alpha; 0/bcl-2-Associated X Protein; EC 1.15.1.1/Superoxide Dismutase; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Casp8 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 8
Comments/Corrections

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