Matrix metalloproteinase-10 protects against acute kidney injury by augmenting epidermal growth factor receptor signaling

Abstract

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.

Matrix Metalloproteinase-10 in Kidney Injury Repair and Disease

“…Contrary to its weak staining in normal human kidney tubular cells [48], MMP-10 is scarcely expressed in normal murine kidneys. It is substantially induced under pathological conditions [7,12]. Consistently, MMP-10-/-mice and transgenic mice with podocyte-specific expression of MMP-10 do not display overt renal abnormality [7,49].…”

“…In response to diverse insults, MMP-10 can be induced in various cells, including the renal tubular epithelium, glomerular podocytes, juxtaglomerular apparatus, as well as renal cell carcinoma [7,12,48,50]. Table 1 shows the expression and localization of MMP-10 in various kidney disorders.…”

“…Induction of MMP-10 is a common pathological finding in various models of AKI. Studies show that MMP-10 protein is substantially upregulated in various animal models of AKI, including ischemia-reperfusion injury (IRI), cisplatin-induced nephrotoxic AKI and glycerol-induced rhabdomyolysis-associated AKI [12,51]. Notably, the mRNA level of MMP-10 is induced as early as 4 h and sustained at least to 48 h after IRI [12].…”

“…The inability to digest type I collagen is the main feature that distinguishes stromelysins from collagenases. Recent studies, however, have uncovered that MMP-10 also participates in regulating a variety of biological processes by cleaving numerous bioactive molecules on the cell surface in of biological processes by cleaving numerous bioactive molecules on the cell surface in the kidney [7,12]. New substrates of MMP-10 have increasingly been identified, such as heparin binding-epidermal growth factor (HB-EGF) and zonula occludens-1 (ZO-1), among others [7,[12][13][14].…”

“…Recent studies, however, have uncovered that MMP-10 also participates in regulating a variety of biological processes by cleaving numerous bioactive molecules on the cell surface in of biological processes by cleaving numerous bioactive molecules on the cell surface in the kidney [7,12]. New substrates of MMP-10 have increasingly been identified, such as heparin binding-epidermal growth factor (HB-EGF) and zonula occludens-1 (ZO-1), among others [7,[12][13][14]. Functionally, MMP-10 can be viewed as a double-edged sword in renal pathophysiology under different circumstances.…”