Matrix metalloproteinase-10 (MMP-10) is a zinc-dependent endopeptidase involved in regulating a wide range of biologic processes, such as apoptosis, cell proliferation, and tissue remodeling. However, the role of MMP-10 in the pathogenesis of acute kidney injury (AKI) is unknown. In this study, we show that MMP-10 was upregulated in the kidneys and predominantly localized in the tubular epithelium in various models of AKI induced by ischemia/reperfusion (IR) or cisplatin. Overexpression of exogenous MMP-10 ameliorated AKI, manifested by decreased serum creatinine, blood urea nitrogen, tubular injury and apoptosis, and increased tubular regeneration. Conversely, knockdown of endogenous MMP-10 expression aggravated kidney injury. Interestingly, alleviation of AKI by MMP-10 in vivo was associated with the activation of epidermal growth factor receptor (EGFR) and its downstream AKT and extracellular signal-regulated kinase-1 and 2 (ERK1/2) signaling. Blockade of EGFR signaling by erlotinib abolished the MMP-10-mediated renal protection after AKI. In vitro, MMP-10 potentiated EGFR activation and protected kidney tubular cells against apoptosis induced by hypoxia/reoxygenation or cisplatin. MMP-10 was colocalized with heparin-binding EGF-like growth factor (HB-EGF) in vivo and activated it by a process of proteolytical cleavage in vitro. These studies identify HB-EGF as a previously unrecognized substrate of MMP-10. Our findings also underscore that MMP-10 can protect against AKI by augmenting EGFR signaling, leading to promotion of tubular cell survival and proliferation after injury.

基质金属蛋白酶-10 (MMP-10) 是一种锌依赖性内肽酶，参与调节多种生物过程，如细胞凋亡、细胞增殖和组织重塑。然而，MMP-10 在急性肾损伤 (AKI) 发病机制中的作用尚不清楚。在这项研究中，我们表明 MMP-10 在肾脏中上调，并且主要位于由缺血/再灌注 (IR) 或顺铂诱导的各种 AKI 模型中的肾小管上皮中。外源性 MMP-10 的过度表达可改善 AKI，表现为血清肌酐、血尿素氮降低、肾小管损伤和凋亡以及肾小管再生增加。相反，内源性 MMP-10 表达的敲低会加重肾损伤。有趣的是，体内 MMP-10 对 AKI 的缓解与表皮生长因子受体 (EGFR) 及其下游 AKT 和细胞外信号调节激酶-1 和 2 (ERK1/2) 信号的激活有关。厄洛替尼对 EGFR 信号的阻断消除了 AKI 后 MMP-10 介导的肾脏保护。在体外，MMP-10 可增强 EGFR 活化并保护肾小管细胞免受缺氧/复氧或顺铂诱导的细胞凋亡。MMP-10 在体内与肝素结合 EGF 样生长因子 (HB-EGF) 共定位，并通过体外蛋白水解裂解过程将其激活。这些研究将 HB-EGF 鉴定为以前未被识别的 MMP-10 底物。我们的研究结果还强调，MMP-10 可以通过增强 EGFR 信号传导来预防 AKI，从而促进损伤后肾小管细胞的存活和增殖。