RRC ID 11827
Author Hayashi K, Sasamura H, Ishiguro K, Sakamaki Y, Azegami T, Itoh H.
Title Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2.
Journal Kidney Int.
Abstract 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.
Volume 78(1)
Pages 69-78
Published 2010-7
DOI 10.1038/ki.2010.81
PII S0085-2538(15)54398-6
PMID 20375993
MeSH Angiotensin II / pharmacology Angiotensin II / therapeutic use Angiotensin Receptor Antagonists* Angiotensins / pharmacology Angiotensins / therapeutic use Animals Antihypertensive Agents / pharmacology Antihypertensive Agents / therapeutic use Benzimidazoles Hypertension / drug therapy Hypertension / pathology Hypertension / physiopathology Kidney / drug effects Kidney / pathology Kidney / physiopathology Kidney Diseases / drug therapy* Kidney Diseases / pathology Kidney Diseases / physiopathology* Kidney Glomerulus / drug effects Kidney Glomerulus / pathology Kidney Glomerulus / physiopathology Matrix Metalloproteinase 2 / pharmacology Matrix Metalloproteinase Inhibitors* Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Knockout Random Allocation Rats Rats, Inbred SHR Receptors, Angiotensin / therapeutic use Tetrazoles Time Factors
IF 8.306
Times Cited 21
Mice GelA KO