Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease indb/dbmice

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.

Akt1-Mediated Fast/Glycolytic Skeletal Muscle Growth Attenuates Renal Damage in Experimental Kidney Disease

“…For example, low-intensity exercise was shown to attenuate the progression of diabetic nephropathy in KK-A (Y) mice 30 and db/db mice. 31 Swimming exercise reduced the progression of renal disease in 5/6 nephrectomized rats. 32 Previous exercise training also protects against the progression of diabetic nephropathy produced by streptozotocin-induced diabetes in rats.…”

DPP-4 inhibition with alogliptin on top of angiotensin II type 1 receptor blockade ameliorates albuminuria <i>via</i> up-regulation of SDF-1α in type 2 diabetic patients with incipient nephropathy

“…Oxidative stress induced by superoxide anion excess is considered a major cause of DN [26][27][28][29]. We have recently reported that renal oxidative stress is highly produced in the incipient DN stage, but not the normoalbuminuric stage, and that the incipient DN stage is more suitable than other stages for antioxidative intervention [30].…”

Altered Glutathione Homeostasis in Heart Augments Cardiac Lipotoxicity Associated with Diet-induced Obesity in Mice

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