A Disintegrin and Metalloenzyme (ADAM) 17 Activation Is Regulated by α5β1 Integrin in Kidney Mesangial Cells

Göőz, Pal; Dang, Yujing; Higashiyama, Shigeki; Twal, Waleed O.; Haycraft, Courtney J.; Göõz, Monika

doi:10.1371/journal.pone.0033350

Cited by 41 publications

(42 citation statements)

References 32 publications

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“…Moreover, our gene silencing studies confirm that uPAR is a negative regulator of TACE in specific keratinocyte populations. Similar results were obtained by Gooz and colleagues (40), who showed that a5b1 integrin binding to TACE in kidney mesangial cells has a significant inhibitory effect on TACE activity. uPAR-TACE interaction may affect TACE conformation, and alter its activity by, for example, blocking substrate (Notch1) binding.…”

Section: Discussionsupporting

confidence: 89%

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Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1

et al. 2015

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Section: Discussionsupporting

confidence: 89%

“…, as described (40). Both TACE activity and NICD levels were increased in uPAR À/À raft and non-raft fractions relative to uPAR þ/þ fractions, where NICD was almost absent, both in the absence and in the presence of TPA ( Supplementary Fig.…”

Section: Uparmentioning

confidence: 68%

Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1

et al. 2015

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“…ADAM17, a member of this ADAM family of MMPs, was originally described as the sheddase of tumor necrosis factor-␣, referred to as TNF␣-converting enzyme (4, 34). In addition, ADAM17 is also responsible for cleaving membrane-bound growth factors and receptors such as transforming growth factor-␣ (TGF␣), heparin-bound epidermal growth factor (HB-EGF), TNF receptor I and II, adhesion molecules, proinflammatory molecules, amyloid precursor protein, and ErbB4 (4,12,17,28,34,39,41).There is evidence that ADAM17 plays a role in the pathogenesis of DN (1,3,10,11,20,21,26,29,33,35,40,42,47,48). Studies in mesangial cells showed that glucose activates ADAM17 and EGF receptor (EGFR) and regulates profibrotic TGF␤ and the accumulation of matrix proteins (48,(51)(52)(53).…”

mentioning

confidence: 99%

ADAM17 mediates Nox4 expression and NADPH oxidase activity in the kidney cortex of OVE26 mice

Ford

Eid

Göõz

et al. 2013

American Journal of Physiology-Renal Physiology

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Ford BM, Eid AA, Göőz M, Barnes JL, Gorin YC, Abboud HE. ADAM17 mediates Nox4 expression and NADPH oxidase activity in the kidney cortex of OVE26 mice. Am J Physiol Renal Physiol 305: F323-F332, 2013. First published May 15, 2013 doi:10.1152/ajprenal.00522.2012.-Matrix protein accumulation is a prominent feature of diabetic nephropathy that contributes to renal fibrosis and decline in renal function. The pathogenic mechanisms of matrix accumulation are incompletely characterized. We investigated if the matrix metalloprotease a disintegrin and metalloprotease1 7 (ADAM17), known to cleave growth factors and cytokines, is activated in the kidney cortex of OVE26 type 1 diabetic mice and the potential mechanisms by which ADAM17 mediates extracellular matrix accumulation. Protein expression and activity of ADAM17 were increased in OVE26 kidney cortex. Using a pharmacological inhibitor to ADAM17, TMI-005, we determined that ADAM17 activation results in increased type IV collagen, Nox4, and NADPH oxidase activity in the kidney cortex of diabetic mice. In cultured mouse proximal tubular epithelial cells (MCTs), high glucose increases ADAM17 activity, Nox4 and fibronectin expression, cellular collagen content, and NADPH oxidase activity. These effects of glucose were inhibited when cells were pretreated with TMI-005 and/or transfected with small interfering ADAM17. Collectively, these data indicate a novel mechanism whereby hyperglycemia in diabetes increases extracellular matrix protein expression in the kidney cortex through activation of ADAM17 and enhanced oxidative stress through Nox enzyme activation. Additionally, our study is the first to provide evidence that Nox4 is downstream of ADAM17. ADAM17; Nox4; diabetic nephropathy; OVE26 mice; extracellular matrix DIABETIC NEPHROPATHY (DN) is characterized by diverse pathophysiological changes in the kidney including extracellular matrix (ECM) accumulation in glomeruli and tubulointerstitium (50). Matrix metalloproteases (MMPs) are a large and diverse family of proteins implicated in regulating ECM turnover and tissue remodeling. Several studies have suggested that metalloproteases contribute to ECM turnover in diabetes. However, relatively little information is available regarding the role of the a disintegrin and a metalloprotease, or ADAM, family of MMPs. Members of this family are modular membrane proteins involved in proteolytic processing or shedding of membrane-bound proteins and receptors (24,25,32,43). ADAM metalloproteases have adhesive and proteolytic properties that modulate cell signaling and biological responses of cells (5,12,19). ADAM17, a member of this ADAM family of MMPs, was originally described as the sheddase of tumor necrosis factor-␣, referred to as TNF␣-converting enzyme (4, 34). In addition, ADAM17 is also responsible for cleaving membrane-bound growth factors and receptors such as transforming growth factor-␣ (TGF␣), heparin-bound epidermal growth factor (HB-EGF), TNF receptor I and II, adhesion molecules, proinflammatory molecules, amyloid pr...

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“…1A). Since activated ADAM17 localizes to the cell surface (8), this finding suggests that in PKD, ADAM17 becomes activated to induce growth factor shedding that can result in sustained upregulation of apical EGFR activity and maintenance of the proliferative phenotype of cystic epithelium. This hypothesis was supported by our in vitro data showing that PKD collecting duct cells had higher ADAM17 expression and activity with a resultant increase in growth factor shedding compared with control cells (Figs.…”

Section: Discussionmentioning

confidence: 98%

“…3A). Second, we assessed shedding of growth factors after transfecting alkaline phosphatase-tagged growth factor constructs (8). The advantage of this method is detection of low concentrations of growth factors in small volumes of culture media.…”

Section: Adam17 Expression and Activity Are Increased In A Model Of Amentioning

confidence: 99%

ADAM17 promotes proliferation of collecting duct kidney epithelial cells through ERK activation and increased glycolysis in polycystic kidney disease

Göõz

Maldonado

Dang

et al. 2014

American Journal of Physiology-Renal Physiology

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Polycystic kidney disease (PKD) is a common genetic disorder leading to cyst formation in the kidneys and other organs that ultimately results in kidney failure and death. Currently, there is no therapy for slowing down or stopping the progression of PKD. In this study, we identified the disintegrin metalloenzyme 17 (ADAM17) as a key regulator of cell proliferation in kidney tissues of conditional knockout Ift88 −/− mice and collecting duct epithelial cells from Ift88° rpk mice, animal models of autosomal recessive polycystic kidney disease (ARPKD). Using Western blotting, an enzyme activity assay, and a growth factor-shedding assay in the presence or absence of the specific ADAM17 inhibitor TMI-005, we show that increased expression and activation of ADAM17 in the cystic kidney and in collecting duct epithelial cells originating from the Ift88° rpk mice (designated as PKD cells) lead to constitutive shedding of several growth factors, including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, and transforming growth factor-α (TGF-α). Increased growth factor shedding induces activation of the EGFR/MAPK/ERK pathway and maintains higher cell proliferation rate in PKD cells compared with control cells. PKD cells also displayed increased lactate formation and extracellular acidification indicative of aerobic glycolysis (Warburg effect), which was blocked by ADAM17 inhibition. We propose that ADAM17 is a key promoter of cellular proliferation in PKD cells by activating the EGFR/ERK axis and a proproliferative glycolytic phenotype.

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A Disintegrin and Metalloenzyme (ADAM) 17 Activation Is Regulated by α5β1 Integrin in Kidney Mesangial Cells

Cited by 41 publications

References 32 publications

Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1

Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1

ADAM17 mediates Nox4 expression and NADPH oxidase activity in the kidney cortex of OVE26 mice

ADAM17 promotes proliferation of collecting duct kidney epithelial cells through ERK activation and increased glycolysis in polycystic kidney disease

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