Submitted on September 16, 2008
Revised on January 8, 2009
Accepted on January 8, 2009
Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice
Sanjoy Ghosh1, Majid Khazaei, Farzad Moien Afshari2, Lisa S. Ang2, David J. Granville3, Bruce Verchere2, Stephen R. Dunn4, Peter McCue5, Andrew Mizisin6, Kumar Sharma7, and Ismail Laher2*
1 UNIVERSITY OF BRITISH COLUMBIA
2 University of British Columbia
3 The Scripps Research Institute
4 Thomas Jefferson University
5 Thomas Jefferson University,
6 University of California, San Diego
7 University of California at San Diego
* To whom correspondence should be addressed. E-mail: ilaher{at}interchange.ubc.ca.
Diabetic nephropathy, the leading cause of end-stage renal disease, is characterized by a pro-apoptotic and pro-oxidative environment. The mechanisms by which lifestyle interventions, such as exercise, benefits 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 weeks, following which renal function, morphology, apoptotic signalling 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-
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 a concurrent 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, may underlie the beneficial effects of exercise in diabetic kidney disease.
