Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits
progression of diabetic renal disease in db/db mice.
Authors Ghosh S, Khazaei M, Moien-Afshari F, Ang LS, Granville DJ, Verchere CB, Dunn SR,
McCue P, Mizisin A, Sharma K, Laher I
Submitted By Oliver Smithies on 3/24/2010
Status Published
Journal American journal of physiology. Renal physiology
Year 2009
Date Published 4/1/2009
Volume : Pages 296(4) : F700 - F708
PubMed Reference 19144689
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.


BaxBcl2-associated X protein
Bcl2B-cell leukemia/lymphoma 2
Casp3caspase 3, apoptosis related cysteine protease
Casp8caspase 8
Casp9caspase 9
Nkx3-1NK-3 transcription factor, locus 1 (Drosophila)
Tnftumor necrosis factor