ADAM17 upregulation in human renal disease: a role in modulating TGF-α availability?

Melenhorst, Wynand B. W. H.; Visser, Lydia; Timmer, Albertus; Heuvel, Marius C. van den; Stegeman, Coen A.; Goor, van Harry

doi:10.1152/ajprenal.90610.2008

Cited by 71 publications

(88 citation statements)

References 37 publications

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“…Initial reports indicate ADAM17 and cleavage of its substrates may be involved in kidney disease and can also contribute to the progression of diabetes (1,3,9,10,15,20,21,26,29,33,35,40,42,45,47). We hypothesized that ADAM17 plays a key role in ECM accumulation in DN.…”

Section: Resultsmentioning

confidence: 98%

“…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).…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 98%

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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“…50 ADAM plays an important role in modulation of cell signaling in physiology and pathophysiology. [50][51][52] Studies on cultured cell and kidney slices indicated that a-secretase (ADAM 10/ 17) and b-secretase modulate aKlotho ectodomain shedding and becoming soluble aKlotho protein, 18,19 by acting on two cleavage sites: one close to the juxtamembrane region (aa 950 approximately981) and another between the KL1 and KL2 domains. 53 To examine if secretases modulate circulating aKlotho in vivo, we injected a-secretase inhibitor doxycline hyclate and/or b-secretase inhibitor III into the intraperitoneal cavity of normal mice for 2 days and determined serum aKlotho in 48 hours.…”

Section: Resultsmentioning

confidence: 99%

Renal Production, Uptake, and Handling of Circulating αKlotho

Shi

Zhang³

et al. 2016

Journal of the American Society of Nephrology

222

254

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ABSTRACTaKlotho is a multifunctional protein highly expressed in the kidney. Soluble aKlotho is released through cleavage of the extracellular domain from membrane aKlotho by secretases to function as an endocrine/paracrine substance. The role of the kidney in circulating aKlotho production and handling is incompletely understood, however. Here, we found higher aKlotho concentration in suprarenal compared with infrarenal inferior vena cava in both rats and humans. In rats, serum aKlotho concentration dropped precipitously after bilateral nephrectomy or upon treatment with inhibitors of aKlotho extracellular domain shedding. Furthermore, the serum half-life of exogenous aKlotho in anephric rats was four-to five-fold longer than that in normal rats, and exogenously injected labeled recombinant aKlotho was detected in the kidney and in urine of rats. Both in vivo (micropuncture) and in vitro (proximal tubule cell line) studies showed that aKlotho traffics from the basal to the apical side of the proximal tubule via transcytosis. Thus, we conclude that the kidney has dual roles in aKlotho homeostasis, producing and releasing aKlotho into the circulation and clearing aKlotho from the blood into the urinary lumen.

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“…These ADAM17-specific staining patterns were in line with a study by Melenhorst et al, who analyzed ADAM17 mRNA distribution in renal diseases. 48 The staining patterns of biopsies from patients with active AAV draw a completely different picture. So far, we could only speculate about the nature of these changes.…”

Section: Discussionmentioning

confidence: 99%

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

Bertram

Lovric

Engel

et al. 2015

Journal of the American Society of Nephrology

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ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasmaderived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.

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ADAM17 upregulation in human renal disease: a role in modulating TGF-α availability?

Cited by 71 publications

References 37 publications

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

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

Renal Production, Uptake, and Handling of Circulating αKlotho

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

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