Upregulation of ADAM19 in Chronic Allograft Nephropathy

Melenhorst, Wynand B. W. H.; Heuvel, Marius C. van den; Stegeman, Coen A.; Leij, Judith van der; Huitema, S.; Berg, Anke van den; Goor, Harry van

doi:10.1111/j.1600-6143.2006.01384.x

Cited by 17 publications

(12 citation statements)

References 32 publications

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“…A similar tubular expression pattern was observed for ADAM19 (19,20), which could implicate redundant roles of ADAMs, which has already been demonstrated for ADAM17 and ADAM19 with regard to HB-EGF shedding (12). The strong distal tubular expression of ADAM17 in healthy kid- Fig.…”

Section: Discussionsupporting

confidence: 73%

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

Melenhorst¹,

Visser²,

Timmer³

et al. 2009

American Journal of Physiology-Renal Physiology

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A disintegrin and metalloproteinase (ADAM)17 sheds growth factors from the cell membrane, including epidermal growth factor receptor (EGFR) ligand transforming growth factor (TGF)-alpha. In mice, angiotensin II infusion induces renal fibrosis via ADAM17-mediated TGF-alpha shedding and subsequent EGFR activation. Pharmacological ADAM17 inhibition reduced renal fibrotic lesions and improved renal function, positioning ADAM17 as a promising target of intervention in renal disease. We studied ADAM17 expression in the human kidney. ADAM17 mRNA was constitutively expressed in normal adult kidneys, with highest expression in distal tubules. In human renal disease, ADAM17 was de novo expressed in proximal tubules, peritubular capillaries, and glomerular mesangium and upregulated in podocytes. Glomerular mesangial and endothelial ADAM17 were associated with mesangial matrix expansion, focal glomerulosclerosis, and glomerular macrophage infiltration (P< 0.01). Peritubular capillary and proximal tubular ADAM17 were associated with interstitial fibrosis and interstitial macrophage infiltration (P < 0.05). Both glomerular and interstitial ADAM17 were associated with decreased renal function (P < 0.05). In renal fibrosis, ADAM17 colocalized with TGF-alpha. Moreover, in cultured human podocytes and proximal tubular cells, pharmacological ADAM17 inhibition reduced constitutive TGF-alpha shedding by 78% (P < 0.005) and 100% (P < 0.05), respectively, and phorbol ester-induced TGF-alpha shedding by 84% (P < 0.005) and 92% (P = 0.005), respectively. Finally, ADAM17 inhibition reduced cellular proliferation. In conclusion, the ADAM17 expression pattern and its role in shedding TGF-alpha from cultured human kidney cells suggest a role in the development of fibrosis. Since EGFR signaling is implicated in renal fibrosis, targeting ADAM17 to reduce availability of EGFR ligand TGF-alpha may represent a promising way of intervention in human renal disease.

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Section: Discussionsupporting

confidence: 73%

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

Melenhorst¹,

Visser²,

Timmer³

et al. 2009

American Journal of Physiology-Renal Physiology

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“…It has become increasingly clear that MMPs and ADAMs have many novel roles in the modulation of the immune response (1–7). In this regard, previous studies have shown increased MMP/ADAM expression in association with allograft rejection (16–27). To further define the role of MMP/ADAM in the process of allograft rejection, we determined the effect of broad‐spectrum MMP/ADAM inhibition on the pathogenesis of allograft rejection.…”

Section: Discussionmentioning

confidence: 97%

“…Recent studies have shown increased expression of MMPs and ADAMs associated with heart, lung and kidney allograft rejection (16–25). In this regard, our previous studies have shown contrasting roles for MMP‐2 and MMP‐9 in allograft rejection (26,27).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Allograft Survival and Modulation of T-Cell Alloreactivity Induced by Inhibition of MMP/ADAM Enzymatic Activity

Eaton

Lerret

Velásquez‐Lopera

et al. 2008

American Journal of Transplantation

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Recent studies have shown significantly increased expression of matrix metalloproteinases (MMP) and disintegrin-type metalloproteinases (ADAM) during allograft rejection. In this regard, our previous studies have demonstrated contrasting roles for MMP-2 and MMP-9 during allograft rejection: MMP-2-deficiency enhanced allograft survival while MMP-9-deficiency decreased allograft survival. The aim of this study was to determine the effect of broad-spectrum MMP/ADAM inhibition on the pathogenesis of allograft rejection. Toward this, heterotopic BALB/c cardiac allografts were transplanted into C57BL/6 recipients treated with MMP/ADAM inhibitors, GM6001 or doxycycline. Systemic MMP/ADAM inhibition significantly enhanced allograft survival. Functioning allografts recovered from MMP/ADAM inhibitor-treated recipients showed lower cellular infiltration and tissue remodeling than rejected allografts recovered from control recipients. In addition, decreased chemotaxis of CD4+ and CD8+ T cells, B cells and macrophages was observed in vitro in the presence of MMP/ADAM inhibitors. Enhanced T-cell alloreactivity was also observed ex vivo in MMP/ADAM inhibitor-treated recipients and in vitro in the presence of MMP/ADAM inhibitors. These observations were associated with enhanced cytokine, chemokine and growth factor production. These results indicate that MMPs and ADAMs play a critical role in the pathogenesis of allograft rejection and may represent novel therapeutic targets for the treatment and/or prevention of this disease.

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“…Pre-clinical and clinical experimental evidence of involvement of extracellular matrix (ECM) protein and proteases in kidney disease [14,53,55-59,63,69-73,77-79,83-86,90], [94,97,99-101,112,113,115,134-154]. …”

Section: Supplementary Materialsmentioning

confidence: 99%

The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis?

Genovese

Manresa

Leeming

et al. 2014

Fibrogenesis Tissue Repair

288

236

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Interstitial fibrosis is the common endpoint of end-stage chronic kidney disease (CKD) leading to kidney failure. The clinical course of many renal diseases, and thereby of CKD, is highly variable. One of the major challenges in deciding which treatment approach is best suited for a patient but also in the development of new treatments is the lack of markers able to identify and stratify patients with stable versus progressive disease. At the moment renal biopsy is the only means of diagnosing renal interstitial fibrosis. Novel biomarkers should improve diagnosis of a disease, estimate its prognosis and assess the response to treatment, all in a non-invasive manner. Existing markers of CKD do not fully and specifically address these requirements and in particular do not specifically reflect renal fibrosis. The aim of this review is to give an insight of the involvement of the extracellular matrix (ECM) proteins in kidney diseases and as a source of potential novel biomarkers of renal fibrosis. In particular the use of the protein fingerprint technology, that identifies neo-epitopes of ECM proteins generated by proteolytic cleavage by proteases or other post-translational modifications, might identify such novel biomarkers of renal fibrosis.

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Upregulation of ADAM19 in Chronic Allograft Nephropathy

Cited by 17 publications

References 32 publications

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

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

Enhanced Allograft Survival and Modulation of T-Cell Alloreactivity Induced by Inhibition of MMP/ADAM Enzymatic Activity

The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis?

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