Increased expression of MMP-2, MMP-9 (type IV collagenases/gelatinases), and MT1-MMP in canine X-linked Alport syndrome (XLAS)
Increased expression of MMP-2, MMP-9 (type IV collagenases/gelatinases), and MT1-MMP in canine X-linked Alport syndrome (XLAS)
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DOI：
10.1046/j.1523-1755.2003.00939.x
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发表时间：
2003-05-01
影响因子：
19.6
通讯作者：
Cosgrove, D
中科院分区：
文献类型：
--
作者：
Rao, VH;Lees, GE;Cosgrove, D
背景Alport综合征是一组由α 3（IV）、α 4（IV）或α 5（IV）胶原蛋白链突变引起的遗传性疾病。该疾病的特征在于进行性肾小球肾炎，通常与高频特异性感音神经性听力损失、斑点视网膜病变和透镜异常相关。具有自然发生的基底膜胶原蛋白（IV型）遗传疾病的狗可以作为Alport综合征的动物模型。在这项研究中，一个良好的特点，自然发生的犬模型，以证明基质金属蛋白酶（MMPs）在Alport肾病发病机制的潜在作用。对发生肾衰竭的青春期雄性犬实施安乐死并进行尸检。采用明胶酶谱法、Western印迹法、原位酶谱法、免疫组化法和逆转录聚合酶链反应（RT-PCR）检测正常和Alport犬肾脏MMP-2、MMP-9和膜型1-MMP（MT 1-MMP）的表达。受影响的犬出现蛋白尿和快速进行性幼年型慢性肾衰竭。Alport肾组织中MMP-2和MMP-9的活性明显升高。原位酶谱证实受影响的狗的肾冷冻切片中活性金属蛋白酶升高。MMP-2、MMP-9和MT 1-MMP mRNA在Alport犬中的表达也增加，提示MMP的表达增加反映了Alport综合征的进展。在X连锁Alport综合征犬的纤维化肾皮质中观察到MMP-2、MMP-9和MT 1-MMP的表达升高。这些结果表明，基质金属蛋白酶可能发挥重要作用，在基质积累与进行性肾瘢痕形成在这个模型中。
Background. Alport syndrome is a group of genetic disorders resulting from mutations in either the alpha3(IV), alpha4(IV) or alpha5(IV) collagen chains. The disease is characterized by a progressive glomerulonephritis, usually associated with a high-frequency specific sensorineural hearing loss, dot and fleck retinopathy, and lens abnormalities. Dogs with naturally occurring genetic disorders of basement membrane collagen (type IV) may serve as animal models of Alport syndrome. In this study, a well-characterized naturally occurring canine model was employed to demonstrate a potential role for matrix metalloproteinases (MMPs) in Alport renal disease pathogenesis.Methods. Adolescent male dogs that developed renal failure were euthanized and necropsied. Clinicopathologic features of the disease were characterized, and kidneys from normal and Alport dogs were analyzed by gelatin zymography, Western blotting, in situ zymography, immunohistology, and by reverse transcription polymerase chain reaction (RT-PCR) for expression of MMP-2, MMP-9, and membrane type 1-MMP (MT1-MMP).Results. Affected dogs developed proteinuria and rapidly progressive juvenile-onset chronic renal failure. The activities of MMP-2 and MMP-9 were significantly induced in Alport kidney. In situ zymography confirmed elevated active metalloproteinases in kidney cryosections of affected dogs. The mRNAs encoding MMP-2, MMP-9 and MT1-MMP were also increased in Alport dogs suggesting that elevated expression of MMPs reflects events in the progression of Alport syndrome in dogs.Conclusion. Elevated expression of MMP-2, MMP-9, and MT1-MMP is observed in fibrotic renal cortex from X-linked Alport syndrome dogs. These findings suggest that MMPs may play an important role in matrix accumulation associated with progressive renal scarring in this model.