Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease.
Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease.
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DOI：
10.1371/journal.pmed.0030100
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发表时间：
2006-04
期刊：
影响因子：
15.8
通讯作者：
Kalluri, Raghu
中科院分区：
文献类型：
--
作者：
Zeisberg, Michael;Khurana, Mona;Rao, Velidi H.;Cosgrove, Dominic;Rougier, Jean-Philippe;Werner, Michelle C.;Shield, Charles F., III;Werb, Zena;Kalluri, Raghu
肾小球基底膜 (GBM) 是肾脏血液过滤装置的关键组成部分，由 IV 型胶原蛋白与层粘连蛋白、巢蛋白和硫酸化蛋白聚糖组装而成。 GBM 中涉及 IV 型胶原蛋白 α3(IV)、α4(IV) 或 α5(IV) 链的突变或缺失已被确定为人类 Alport 综合征的病因，Alport 综合征是一种与耳聋相关的进行性遗传性肾病。这种突变导致最终肾衰竭的病理机制尚不完全清楚。我们发现，有缺陷的人类 Alport GBM 对蛋白水解降解的敏感性增加是由三种不同的基质金属蛋白酶 (MMP)（MMP-2、MMP-3 和 MMP-9）介导的，这会影响 α3(IV) −/− 小鼠（人类 Alport 综合征模型）肾功能障碍的进展。 MMP-2 或 MMP-9 或 MMP-2 和 MMP-9 的基因消融会导致肾小球中其他 MMP 的代偿性上调。在 α3(IV) -/− 小鼠出现蛋白尿或 GBM 结构缺陷之前，对与多种 GBM 降解 MMP 相关的酶活性进行药物消除，可显着减弱与延迟性蛋白尿相关的疾病进展，并显着延长生存期。相反，诱导蛋白尿后抑制MMP会导致与广泛间质纤维化相关的疾病加速以及α3(IV) -/− 小鼠的早期死亡。 这些结果表明，在蛋白尿发作前保持 GBM/细胞外基质的完整性可带来显着的疾病保护作用，但如果失去这个机会，Alport 病后期的 MMP 抑制会导致肾小球和间质纤维化加速。我们的研究结果确定了 MMP 在 α3(IV) −/− 小鼠 Alport 病进展中的关键双重作用，具有早期致病功能和后期保护作用。因此，我们建议在出现蛋白尿之前，可以使用 MMP 抑制剂作为具有已知遗传缺陷的 Alport 综合征患者的疾病预防药物。 在阿尔波特病小鼠模型中，基质金属蛋白酶似乎在疾病进展中发挥着至关重要的双重作用，具有早期致病功能和后期保护作用。
Glomerular basement membrane (GBM), a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving α3(IV), α4(IV), or α5(IV) chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood. We showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs)—MMP-2, MMP-3, and MMP-9—which influence the progression of renal dysfunction in α3(IV) −/− mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the α3(IV) −/− mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of α3(IV) −/− mice. These results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in α3(IV) −/− mice, with an early pathogenic function and a later protective action. Hence, we propose possible use of MMP-inhibitors as disease-preventive drugs for patients with Alport syndrome with identified genetic defects, before the onset of proteinuria. In a mouse model of Alport disease, matrix metalloproteinases appear to have a crucial dual role in disease progression, with an early pathogenic function and a later protective action.
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