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Physical exercise training but not metformin attenuates albuminuria and shedding of ACE2 in type 2 diabetic db/db mice

Somineni, Hari Krishna
http://rave.ohiolink.edu/etdc/view?acc_num=wright1369704228

Abstract Details

2013, Master of Science (MS), Wright State University, Pharmacology and Toxicology.
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.
Khalid Elased, Pharm D, Ph.D. (Advisor)
Gregory Boivin, D.V.M. (Committee Member)
Courtney Sulentic, Ph.D. (Committee Member)
125 p.
Animal Diseases; Animal Sciences; Pharmacology
Urinary ACE2; Albuminuria; Biomarkers; Diabetic nephropathy; ADAM17; Timp3; Collagen; PAS staining; type 2 diabetes; db/db mice; Physical exercise training; Metformin

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Citations

  • Somineni, H. K. (2013). Physical exercise training but not metformin attenuates albuminuria and shedding of ACE2 in type 2 diabetic db/db mice [Master's thesis, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright1369704228

    APA Style (7th edition)

  • Somineni, Hari Krishna. Physical exercise training but not metformin attenuates albuminuria and shedding of ACE2 in type 2 diabetic db/db mice. 2013. Wright State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=wright1369704228.

    MLA Style (8th edition)

  • Somineni, Hari Krishna. "Physical exercise training but not metformin attenuates albuminuria and shedding of ACE2 in type 2 diabetic db/db mice." Master's thesis, Wright State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=wright1369704228

    Chicago Manual of Style (17th edition)

wright1369704228
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© 2013, all rights reserved.
This open access ETD is published by Wright State University and OhioLINK.