Higher doses of AngII (angiotensin II) blockers are intended to optimize albuminuria reduction rather than for blood pressure control in chronic kidney disease. However, the long-term renoprotection of high-dose AngII blockers has yet to be defined. The present study sought to determine whether doses of ARB (AngII receptor blocker) that maximally reduce proteinuria could slow the progression of glomerulosclerosis in the uninephrectomized db/db mouse, a model of Type 2 diabetes. Untreated uninephrectomized db/db mice had normal blood pressure, but developed progressive albuminuria and mesangial matrix expansion between 18 and 22 weeks of age, which was associated with increased renal expression of TGFβ1 (transforming growth factor β1), PAI-1 (plasminogen-activator inhibitor-1), type IV collagen and FN (fibronectin). Treatment with valsartan in the drinking water of db/db mice from 18 to 22 weeks of age, at a dose that was determined previously to maximally reduce proteinuria, prevented the increases in albuminuria and the markers of renal fibrosis seen in untreated db/db mice. In addition, WT-1 (Wilms tumour protein-1)-immunopositive podocyte numbers were found to be lower in the untreated glomeruli of mice with diabetes. The expression of podocin and nephrin were continually decreased in mice with diabetes between 18 and 22 weeks of age. These changes are indicative of podocyte injury and the administration of valsartan ameliorated them substantially. Renal expression of TNFα (tumour necrosis factor α), MCP-1 (monocyte chemoattractant protein-1), Nox2 (NADPH oxidase 2), p22phox and p47phox and urine TBARS (thiobarbituric acid-reacting substance) levels, the markers of renal inflammation and oxidative stress, were increased during disease progression in mice with diabetes. Valsartan treatment was shown to reduce these markers. Thus high doses of valsartan not only reduce albuminuria maximally, but also halt the progression of the glomerulosclerosis resulting from Type 2 diabetes via a reduction in podocyte injury and renal oxidative stress and inflammation.
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Research Article|
January 27 2014
Valsartan slows the progression of diabetic nephropathy in db/db mice via a reduction in podocyte injury, and renal oxidative stress and inflammation
Guangyu Zhou;
*Division of Nephrology, Department of Internal Medicine, Shengjing Hospital, China Medical University, 36 Sanhao Avenue, Heping District, Shenyang 110004, China
†Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, U.S.A.
Correspondence: Dr Guangyu Zhou (email [email protected]) or Dr Yufeng Huang (email [email protected]).
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Alfred K. Cheung;
Alfred K. Cheung
†Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, U.S.A.
‡Medical Care Center, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, UT 84148, U.S.A.
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Xia Liu;
Xia Liu
†Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, U.S.A.
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Yufeng Huang
†Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, U.S.A.
Correspondence: Dr Guangyu Zhou (email [email protected]) or Dr Yufeng Huang (email [email protected]).
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Publisher: Portland Press Ltd
Received:
May 10 2013
Revision Received:
October 11 2013
Accepted:
November 06 2013
Accepted Manuscript online:
November 06 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2014 Biochemical Society
2014
Clin Sci (Lond) (2014) 126 (10): 707–720.
Article history
Received:
May 10 2013
Revision Received:
October 11 2013
Accepted:
November 06 2013
Accepted Manuscript online:
November 06 2013
Citation
Guangyu Zhou, Alfred K. Cheung, Xia Liu, Yufeng Huang; Valsartan slows the progression of diabetic nephropathy in db/db mice via a reduction in podocyte injury, and renal oxidative stress and inflammation. Clin Sci (Lond) 1 May 2014; 126 (10): 707–720. doi: https://doi.org/10.1042/CS20130223
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