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- Publisher Website: 10.1172/JCI97650
- Scopus: eid_2-s2.0-85045062661
- PMID: 29369823
- WOS: WOS:000431958600021
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Article: iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling
Title | iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling |
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Authors | |
Issue Date | 2018 |
Citation | Journal of Clinical Investigation, 2018, v. 128, n. 4, p. 1397-1412 How to Cite? |
Abstract | © 2018 American Society for Clinical Investigation. All rights reserved. Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney diseases. Here, we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-doublestranded DNA (anti-dsDNA) Ab production by simultaneously blocking HB-EGF/EGFR and TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b-/- mice, alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b-/- mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a target for selective and simultaneous dual inhibition of 2 major pathological pathways in the effector arm of the disease. |
Persistent Identifier | http://hdl.handle.net/10722/293082 |
ISSN | 2023 Impact Factor: 13.3 2023 SCImago Journal Rankings: 4.833 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Qing, Xiaoping | - |
dc.contributor.author | Chinenov, Yurii | - |
dc.contributor.author | Redecha, Patricia | - |
dc.contributor.author | Madaio, Michael | - |
dc.contributor.author | Roelofs, Joris J.T.H. | - |
dc.contributor.author | Farber, Gregory | - |
dc.contributor.author | Issuree, Priya D. | - |
dc.contributor.author | Donlin, Laura | - |
dc.contributor.author | Mcllwain, David R. | - |
dc.contributor.author | Mak, Tak W. | - |
dc.contributor.author | Blobel, Carl P. | - |
dc.contributor.author | Salmon, Jane E. | - |
dc.date.accessioned | 2020-11-17T14:57:50Z | - |
dc.date.available | 2020-11-17T14:57:50Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | Journal of Clinical Investigation, 2018, v. 128, n. 4, p. 1397-1412 | - |
dc.identifier.issn | 0021-9738 | - |
dc.identifier.uri | http://hdl.handle.net/10722/293082 | - |
dc.description.abstract | © 2018 American Society for Clinical Investigation. All rights reserved. Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney diseases. Here, we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-doublestranded DNA (anti-dsDNA) Ab production by simultaneously blocking HB-EGF/EGFR and TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b-/- mice, alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b-/- mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a target for selective and simultaneous dual inhibition of 2 major pathological pathways in the effector arm of the disease. | - |
dc.language | eng | - |
dc.relation.ispartof | Journal of Clinical Investigation | - |
dc.title | iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1172/JCI97650 | - |
dc.identifier.pmid | 29369823 | - |
dc.identifier.pmcid | PMC5873859 | - |
dc.identifier.scopus | eid_2-s2.0-85045062661 | - |
dc.identifier.volume | 128 | - |
dc.identifier.issue | 4 | - |
dc.identifier.spage | 1397 | - |
dc.identifier.epage | 1412 | - |
dc.identifier.eissn | 1558-8238 | - |
dc.identifier.isi | WOS:000431958600021 | - |
dc.identifier.issnl | 0021-9738 | - |