PMID- 24195695
OWN - NLM
STAT- MEDLINE
DCOM- 20140402
LR  - 20220716
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Linking)
VI  - 126
IP  - 10
DP  - 2014 May
TI  - Valsartan slows the progression of diabetic nephropathy in db/db mice via a 
      reduction in podocyte injury, and renal oxidative stress and inflammation.
PG  - 707-20
LID - 10.1042/CS20130223 [doi]
AB  - 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 TGFbeta1 (transforming growth factor beta1), 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 TNFalpha (tumour necrosis factor alpha), 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.
FAU - Zhou, Guangyu
AU  - Zhou G
FAU - Cheung, Alfred K
AU  - Cheung AK
FAU - Liu, Xia
AU  - Liu X
AD  - daggerDivision of Nephrology and Hypertension, Department of Internal Medicine, 
      University of Utah School of Medicine, Salt Lake City, UT 84108, U.S.A.
FAU - Huang, Yufeng
AU  - Huang Y
AD  - daggerDivision of Nephrology and Hypertension, Department of Internal Medicine, 
      University of Utah School of Medicine, Salt Lake City, UT 84108, U.S.A.
LA  - eng
GR  - K01 DK077955/DK/NIDDK NIH HHS/United States
GR  - R21 DK081815/DK/NIDDK NIH HHS/United States
GR  - R21DK081815/DK/NIDDK NIH HHS/United States
GR  - K01DK077955/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (Extracellular Matrix Proteins)
RN  - 0 (Fibronectins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (NPHS2 protein)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tetrazoles)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (WT1 Proteins)
RN  - 0 (nephrin)
RN  - 80M03YXJ7I (Valsartan)
RN  - HG18B9YRS7 (Valine)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Experimental/drug therapy/genetics/pathology
MH  - Diabetic Nephropathies/complications/*drug therapy/genetics/pathology
MH  - *Disease Progression
MH  - Extracellular Matrix Proteins/genetics/metabolism
MH  - Fibronectins/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Inflammation/complications/drug therapy/genetics/*pathology
MH  - Intracellular Signaling Peptides and Proteins/genetics/metabolism
MH  - Kidney/drug effects/metabolism/*pathology
MH  - Kidney Cortex/drug effects/metabolism/pathology
MH  - Kidney Glomerulus/drug effects/metabolism/pathology
MH  - Membrane Proteins/genetics/metabolism
MH  - Mice
MH  - *Oxidative Stress/drug effects
MH  - Plasminogen Activator Inhibitor 1/genetics/metabolism
MH  - Podocytes/drug effects/metabolism/*pathology
MH  - RNA, Messenger/genetics/metabolism
MH  - Tetrazoles/pharmacology/*therapeutic use
MH  - Transforming Growth Factor beta1/genetics/metabolism
MH  - Treatment Outcome
MH  - Valine/*analogs & derivatives/pharmacology/therapeutic use
MH  - Valsartan
MH  - WT1 Proteins/genetics/metabolism
EDAT- 2013/11/08 06:00
MHDA- 2014/04/03 06:00
CRDT- 2013/11/08 06:00
PHST- 2013/11/08 06:00 [entrez]
PHST- 2013/11/08 06:00 [pubmed]
PHST- 2014/04/03 06:00 [medline]
AID - CS20130223 [pii]
AID - 10.1042/CS20130223 [doi]
PST - ppublish
SO  - Clin Sci (Lond). 2014 May;126(10):707-20. doi: 10.1042/CS20130223.