Angiotensin II (Ang II) is involved in induction and progression of renal damage in diabetes.
Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and has been shown to be renoprotective by degrading Ang II to Ang-(1-7). A
disintegrin and
metalloproteinase 17 (ADAM17)-mediated shedding of renal ACE2 contribute to
diabetic nephropathy pathogenesis. Lifestyle modification and
metformin are recommended as initial
therapies for most patients with
type 2 diabetes. The aim of this study was to investigate whether exercise training and/or
metformin improve
glucose homeostasis and
albuminuria and downregulate renal ADAM17 and ACE2 shedding in db/db mice. Seven-week-old normal and db/db mice were subjected either to a sedentary existence or exercise training with and without
metformin (150 mg/kg per day) for 10 weeks. Exercise training significantly lowered
blood glucose, urinary
albumin and ACE2 excretion in db/db mice. ADAM17 and ACE2
proteins were co-localized in cortical tubules of the kidney, indicating a possible interaction.
Metformin treatment was effective in lowering
hyperglycemia only during the first 2 weeks of treatment. Increased renal ADAM17 in 17-week-old db/db mice was corrected by physical exercise but not
metformin. In addition, exercise training reduced plasma
triglycerides and enhanced
insulin levels of db/db mice. In conclusion, exercise training alone and in combination with
metformin prevented shedding of renal ACE2 by decreasing
ADAM17 protein. Urinary ACE2 could serve as a prognostic tool for the progression of kidney damage and its attenuation by exercise may partially contribute to its renal protection.