Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Institute for Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
JCI Insight. 2016 Aug 18;1(13). doi: 10.1172/jci.insight.87023.
Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor-treated WT mice, or mice with inducible KO of ADAM17 in proximal tubule (Slc34a1-Cre) were significantly protected against these effects. In vitro, in proximal tubule cells, we show that AREG has unique profibrotic actions that are potentiated by TNFα-induced AREG cleavage. In vivo, in acute kidney injury (AKI) and chronic kidney disease (CKD, fibrosis) patients, soluble AREG is indeed highly upregulated in human urine, and both ADAM17 and AREG expression show strong positive correlation with fibrosis markers in related kidney biopsies. Our results indicate that targeting of the ADAM17 pathway represents a therapeutic target for human kidney fibrosis.
肾损伤后的肾纤维化是一个未解决的健康问题，在全球范围内导致了显著的发病率和死亡率。在一项对其分子机制的研究中，我们确定了一些基本的致病特征。急性或慢性肾损伤会导致解整合素金属蛋白酶 17（ADAM17）持续升高；其裂解激活的前配体底物，特别是前 TNFα 和表皮生长因子受体配体 Amphiregulin（前 AREG）；以及这些底物的受体。因此，EGFR 持续激活并触发促炎和促纤维化因子的合成和释放，导致巨噬细胞/中性粒细胞浸润和纤维化。ADAM17 功能不全的小鼠、特异性 ADAM17 抑制剂处理的 WT 小鼠或近端肾小管中诱导型 ADAM17 KO （Slc34a1-Cre）的小鼠对这些影响有显著的保护作用。在体外，在近端肾小管细胞中，我们表明 AREG 具有独特的促纤维化作用，这种作用可被 TNFα 诱导的 AREG 裂解增强。在体内，在急性肾损伤（AKI）和慢性肾脏病（CKD，纤维化）患者中，人尿中可溶性 AREG 确实高度上调，并且 ADAM17 和 AREG 的表达与相关肾活检中的纤维化标志物呈强烈正相关。我们的结果表明，靶向 ADAM17 途径代表了人类肾纤维化的治疗靶点。
