Document Detail

Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2.
MedLine Citation:
PMID:  20375993     Owner:  NLM     Status:  MEDLINE    
Understanding mechanisms that contribute to the regression of glomerulosclerosis is important for developing new strategies to treat chronic kidney disease. We reported that transient high-dose treatment with an angiotensin receptor blocker causes regression of renal arteriolar hypertrophy and hypertension in spontaneously hypertensive rats. To extend those findings to another form of kidney disease, we examined the short- and long-term effects of transient high-dose angiotensin receptor blocker treatment in a mouse model of adriamycin-induced glomerulosclerosis. A 2-week course of candesartan caused a dose-dependent regression of established glomerulosclerotic lesions sustained for over 6 months following cessation of treatment. Highly sensitive in situ zymography and activity assays showed that glomerular matrix metalloproteinase (MMP)-2 activity was increased after high-dose angiotensin blocker therapy. Treatment of cultured podocytes with candesartan resulted in an increase in MMP-2 activity. The regression of glomerulosclerosis was partially attenuated in mice pretreated with the MMP inhibitor doxycycline, as well as in MMP-2 knockout mice. Our results suggest that transient high-dose angiotensin receptor blocker treatment effectively induced sustained regression of glomerulosclerosis by a mechanism mediated, in part, by changes in MMP-2 activity.
Kaori Hayashi; Hiroyuki Sasamura; Kimiko Ishiguro; Yusuke Sakamaki; Tatsuhiko Azegami; Hiroshi Itoh
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-04-07
Journal Detail:
Title:  Kidney international     Volume:  78     ISSN:  1523-1755     ISO Abbreviation:  Kidney Int.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-16     Completed Date:  2010-09-22     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  69-78     Citation Subset:  IM    
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
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MeSH Terms
Angiotensin II / pharmacology,  therapeutic use
Angiotensin Receptor Antagonists*
Angiotensins / pharmacology,  therapeutic use
Antihypertensive Agents / pharmacology,  therapeutic use
Hypertension / drug therapy,  pathology,  physiopathology
Kidney / drug effects,  pathology,  physiopathology
Kidney Diseases / drug therapy*,  pathology,  physiopathology*
Kidney Glomerulus / drug effects,  pathology,  physiopathology
Matrix Metalloproteinase 2 / pharmacology
Matrix Metalloproteinase Inhibitors*
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Knockout
Random Allocation
Rats, Inbred SHR
Receptors, Angiotensin / therapeutic use
Time Factors
Reg. No./Substance:
0/Angiotensin Receptor Antagonists; 0/Angiotensins; 0/Antihypertensive Agents; 0/Benzimidazoles; 0/Matrix Metalloproteinase Inhibitors; 0/Receptors, Angiotensin; 0/Tetrazoles; 11128-99-7/Angiotensin II; EC Metalloproteinase 2; S8Q36MD2XX/candesartan

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