Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2
Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2
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DOI：
10.1038/ki.2010.81
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发表时间：
2010-07-01
影响因子：
19.6
通讯作者：
Itoh, Hiroshi
中科院分区：
文献类型：
--
作者：
Hayashi, Kaori;Sasamura, Hiroyuki;Itoh, Hiroshi
了解有助于肾小球硬化消退的机制对于制定治疗慢性肾脏病的新策略非常重要。我们报道，用血管紧张素受体阻滞剂短暂高剂量治疗可导致自发性高血压大鼠的肾小动脉肥大和高血压消退。为了将这些发现扩展到另一种形式的肾脏疾病，我们在阿霉素诱导的肾小球硬化小鼠模型中检查了短暂大剂量血管紧张素受体阻滞剂治疗的短期和长期影响。坎地沙坦两周疗程可使已形成的肾小球硬化病变出现剂量依赖性消退，这种消退在停止治疗后持续超过 6 个月。高灵敏原位酶谱和活性测定表明，高剂量血管紧张素阻滞剂治疗后肾小球基质金属蛋白酶（MMP）-2 活性增加。用坎地沙坦处理培养的足细胞导致 MMP-2 活性增加。在用 MMP 抑制剂多西环素预处理的小鼠以及 MMP-2 敲除小鼠中，肾小球硬化的消退部分减弱。我们的结果表明，短暂的大剂量血管紧张素受体阻滞剂治疗可通过部分由 MMP-2 活性变化介导的机制有效诱导肾小球硬化的持续消退。肾脏国际 (2010) 78, 69-78; doi：10.1038/ki.2010.81； 2010 年 4 月 7 日在线发布
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. Kidney International (2010) 78, 69-78; doi: 10.1038/ki.2010.81; published online 7 April 2010