Experimental diabetic nephropathy is accelerated in matrix metalloproteinase-2 knockout mice.
Experimental diabetic nephropathy is accelerated in matrix metalloproteinase-2 knockout mice.
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DOI：
10.1093/ndt/gfs387
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发表时间：
2013
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影响因子：
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通讯作者：
Y. Takamiya;K. Fukami;S. Yamagishi;Y. Kaida;Yosuke Nakayama;Nana Obara;Ryuji Iwatani;Ryotaro Ando;Kiyomi Koike;T. Matsui;Yuri Nishino;S. Ueda;M. Cooper;S. Okuda
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文献类型：
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作者：
Y. Takamiya;K. Fukami;S. Yamagishi;Y. Kaida;Yosuke Nakayama;Nana Obara;Ryuji Iwatani;Ryotaro Ando;Kiyomi Koike;T. Matsui;Yuri Nishino;S. Ueda;M. Cooper;S. Okuda
基质金属蛋白酶-2（MMP-2）负责降解各种类型的细胞外基质（ECM）蛋白，如IV型胶原。MMP-2表达和活性的降低通常被认为是糖尿病肾病晚期ECM积累增加的原因。然而，MMP-2在糖尿病肾病早期阶段的动力学和作用仍不清楚。为了解决这个问题，我们研究了链脲佐菌素（STZ）诱导的早期糖尿病肾病是否会在MMP-2敲除（KO）小鼠中加速。方法采用链脲佐菌素（STZ）诱导6周龄正常小鼠和MMP-2基因敲除小鼠糖尿病模型。糖尿病16周后或单独观察后处死动物。结果与非糖尿病对照组相比，16周龄糖尿病小鼠肾脏MMP-2的表达和活性明显增加。与野生型糖尿病同窝小鼠相比，糖尿病MMP-2 KO小鼠的血清尿素氮和肌酐水平以及尿白蛋白和N-乙酰-β-D-氨基葡萄糖苷酶排泄水平显著升高。此外，在糖尿病MMP-2 KO小鼠中，肾小球中ECM的积聚以及肾小管中的萎缩和纤维化加剧，并且肾脏α-平滑肌肌动蛋白表达增强。结论糖尿病肾病早期肾脏MMP-2表达和活性增高是一种代偿机制。由于MMP-2可以对糖尿病肾病的进展起保护作用，因此进一步增强肾脏中MMP-2的表达和/或活性可能是治疗早期糖尿病肾病的治疗靶点。
BACKGROUND Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice. METHODS Diabetes was induced by the injection of STZ in 6-week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone. RESULTS Compared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabetic mice. Serum levels of blood urea nitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-β-D-glucosaminidase were significantly elevated in diabetic MMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal α-smooth muscle actin expression was enhanced in diabetic MMP-2 KO mice. CONCLUSIONS Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy.