Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Kidney Int. 2010 Jul;78(1):69-78. doi: 10.1038/ki.2010.81. Epub 2010 Apr 7.
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.
了解导致肾小球硬化消退的机制对于开发治疗慢性肾病的新策略非常重要。我们曾报道，血管紧张素受体阻滞剂的短期高剂量治疗可导致自发性高血压大鼠的肾小动脉肥厚和高血压消退。为了将这些发现扩展到另一种肾脏疾病，我们在阿霉素诱导的肾小球硬化的小鼠模型中检查了短期和长期的血管紧张素受体阻滞剂高剂量治疗的效果。坎地沙坦 2 周疗程可导致已建立的肾小球硬化病变进行剂量依赖性消退，停药后持续超过 6 个月。高度敏感的原位酶谱法和活性测定显示，肾小球基质金属蛋白酶（MMP）-2 活性在高剂量血管紧张素阻断剂治疗后增加。坎地沙坦处理的培养足细胞导致 MMP-2 活性增加。预先用 MMP 抑制剂强力霉素处理的小鼠以及 MMP-2 敲除小鼠，肾小球硬化的消退部分减弱。我们的结果表明，短暂的高剂量血管紧张素受体阻滞剂治疗通过部分由 MMP-2 活性变化介导的机制，有效地诱导了肾小球硬化的持续消退。
