A possible role for metalloproteinases in renal cyst development
A possible role for metalloproteinases in renal cyst development
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DOI：
10.1152/ajprenal.2001.280.3.f540
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发表时间：
2001-03-01
影响因子：
4.2
通讯作者：
Witzgall, R
中科院分区：
文献类型：
--
作者：
Obermüller, N;Morente, N;Witzgall, R
多囊肾的囊性扩张与良性肿瘤对细胞外基质的侵袭有几个相似之处。因此，我们假设囊肿衬里上皮细胞产生细胞外基质降解金属蛋白酶，这些酶的抑制可能是治疗干预的潜在靶点。应用原位杂交技术，首先分析了常染色体显性遗传性多囊肾病(Cy/+)大鼠肾脏组织中基质金属蛋白酶-14及其抑制物TIMP-2和细胞因子转化生长因子-β2的表达。上调的基质金属蛋白酶-14主要位于囊壁上皮细胞和远端小管，而TIMP-2mRNA几乎仅限于成纤维细胞。囊壁上皮细胞也表达了一种调节基质金属蛋白酶及其抑制物表达的细胞因子--转化生长因子-β2。然后，我们用金属蛋白酶抑制剂batimastat治疗(Cy/+)大鼠8wk。用金属蛋白酶抑制剂贝替马斯特治疗后，囊肿数和肾脏重量显著减少。我们的研究表明，金属蛋白酶抑制剂是治疗多囊肾病的一种新的治疗工具，应该独立于疾病的背景而适用。
The expansion of cysts in polycystic kidneys bears several similarities to the invasion of the extracellular matrix by benign tumors. We therefore hypothesized that cyst-lining epithelial cells produce extracellular matrix-degrading metalloproteinases and that the inhibition of these enzymes may represent a potential target for therapeutic intervention. Using in situ hybridization, we first analyzed the expression of membrane-type metalloproteinase 1 (MMP-14), an essential matrix metalloproteinase, of its inhibitor TIMP-2, and of the cytokine transforming growth factor (TGF)-beta2 in the (cy/+) rat model of autosomal-dominant polycystic kidney disease. Upregulated MMP-14 mRNA was predominantly located in cyst-lining epithelia and distal tubules, whereas TIMP-2 mRNA was confined almost exclusively to fibroblasts. TGF-beta2, a cytokine known to regulate the expression of matrix metalloproteinases and their inhibitors, was also expressed by cyst wall epithelia. We then treated (cy/+) rats with the metalloproteinase inhibitor batimastat for a period of 8 wk. The treatment with the metalloproteinase inhibitor batimastat resulted in a significant reduction of cyst number and kidney weight. Our study suggests that metalloproteinase inhibitors represent a new therapeutic tool against polycystic kidney disease, which should be applicable independently of the background of the disease.