Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2

Kaori Hayashi, Hiroyuki Sasamura, Kimiko Ishiguro, Yusuke Sakamaki, Tatsuhiko Azegami, Hiroshi Itoh

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)69-78
Number of pages10
JournalKidney International
Volume78
Issue number1
DOIs
Publication statusPublished - 2010 Jul

Fingerprint

Matrix Metalloproteinase 2
Angiotensin II
Angiotensin Receptor Antagonists
Therapeutics
Podocytes
Withholding Treatment
Matrix Metalloproteinase Inhibitors
Doxycycline
Angiotensins
Kidney Diseases
Inbred SHR Rats
Chronic Renal Insufficiency
Knockout Mice
Doxorubicin
Hypertrophy
Hypertension
Kidney
candesartan

Keywords

  • Angiotensin receptor blocker
  • Glomerulosclerosis
  • Matrix metalloproteinase

ASJC Scopus subject areas

  • Nephrology
  • Medicine(all)

Cite this

Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2. / Hayashi, Kaori; Sasamura, Hiroyuki; Ishiguro, Kimiko; Sakamaki, Yusuke; Azegami, Tatsuhiko; Itoh, Hiroshi.

In: Kidney International, Vol. 78, No. 1, 07.2010, p. 69-78.

Research output: Contribution to journalArticle

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