Publication Date

2013

Document Type

Thesis

Committee Members

Gregory Boivin (Committee Member), Khalid Elased (Advisor), Courtney Sulentic (Committee Member)

Degree Name

Master of Science (MS)

Abstract

Angiotensin II (Ang II), a potent vasoconstrictor cleaved from Ang I, is responsible for 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 Metalloproteinases (ADAMs) were recently identified as an ectodomain sheddases of transmembrane proteins. ADAM17 mediated shedding of renal ACE2 could contribute to the pathogenesis of diabetic nephropathy. In our previous study, rosiglitazone treatment normalized hyperglycemia and improved renal injury by preventing ACE2 shedding. The aim of this study is to test the hypothesis that improved glucose homeostasis with exercise and/or metformin attenuates albuminuria, renal ADAM17 protein and prevents shedding of ACE2 in db/db mice. Seven week old normal and db/db mice were subjected to physical exercise training and/or metformin treatment (150 mg/kg/day) for 10 weeks. Exercised mice ran on a mouse forced exercise walking wheel system for 1 hr a day for 7 days a week at a speed of 8 meters/minute. At juvenile stages (6 week old), db/db mice demonstrated higher levels of blood glucose, urinary albumin and ACE2 excretion. Urinary ACE2 is enzymatically active and 20 kDa shorter as demonstrated by immunoblotting. Renal ADAM17 and ACE2 protein levels were significantly upregulated in db/db mice compared to non-diabetic controls. In diabetic kidney, upregulated ADAM17 and ACE2 proteins co-localized in the tubular cortex. However, physical exercise training significantly attenuated blood glucose, urinary albumin and ACE2 excretion of db/db mice throughout the study period, whereas metformin treatment was effective in lowering hyperglycemia only in the initial stages of diabetes. The increased renal ADAM17 protein levels in db/db diabetic mice were normalized by exercise training but not by metformin. In addition, exercise training reduced plasma triglycerides and enhanced insulin levels of db/db mice. The combination of exercise and metformin was effective against lowering plasma glucagon. Results demonstrated a significant association between blood glucose, urinary albumin, plasma insulin, glucagon and triglycerides with urinary ACE2 excretion. In conclusion, co-localization of ADAM17 with ACE2 suggests a possible interaction in diabetic kidney. Exercise training with or without metformin prevented shedding of renal ACE2 by attenuating ADAM17 protein. Elevated plasma insulin by exercise could be responsible for improved glucose homeostasis, at least in partial. Urinary ACE2 could serve as a prognostic tool in the progression of kidney damage and its attenuation by exercise may partially contribute to its renal protection.

Page Count

125

Department or Program

Department of Pharmacology and Toxicology

Year Degree Awarded

2013

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