Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis
dc.contributor.author | Gerritsen, KGF | |
dc.contributor.author | Bovenschen, N | |
dc.contributor.author | Nguyen, TQ | |
dc.contributor.author | Sprengers, D | |
dc.contributor.author | Koeners, MP | |
dc.contributor.author | van Koppen, AN | |
dc.contributor.author | Joles, JA | |
dc.contributor.author | Goldschmeding, R | |
dc.contributor.author | Kok, RJ | |
dc.date.accessioned | 2018-12-04T11:45:08Z | |
dc.date.issued | 2016-09-19 | |
dc.description.abstract | CCN-2 (connective tissue growth factor; CTGF) is a key factor in fibrosis. Plasma CCN-2 has biomarker potential in numerous fibrotic disorders, but it is unknown which pathophysiological factors determine plasma CCN-2 levels. The proteolytic amino-terminal fragment of CCN-2 is primarily eliminated by the kidney. Here, we investigated elimination and distribution profiles of full length CCN-2 by intravenous administration of recombinant CCN-2 to rodents. After bolus injection in mice, we observed a large initial distribution volume (454 mL/kg) and a fast initial clearance (120 mL/kg/min). Immunosorbent assay and immunostaining showed that CCN-2 distributed mainly to the liver and was taken up by hepatocytes. Steady state clearance in rats, determined by continuous infusion of CCN-2, was fast (45 mL/kg/min). Renal CCN-2 clearance, determined by arterial and renal vein sampling, accounted for only 12 % of total clearance. Co-infusion of CCN-2 with receptor-associated protein (RAP), an antagonist of LDL-receptor family proteins, showed that RAP prolonged CCN-2 half-life and completely prevented CCN-2 internalization by hepatocytes. This suggests that hepatic uptake of CCN-2 is mediated by a RAP-sensitive mechanism most likely involving LRP1, a member of the LDL-receptor family involved in hepatic clearance of various plasma proteins. Surface plasmon resonance binding studies confirmed that CCN-2 is an LRP1 ligand. Co-infusion of CCN-2 with an excess of the heparan sulphate-binding protamine lowered the large initial distribution volume of CCN-2 by 88 % and reduced interstitial staining of CCN-2, suggesting binding of CCN-2 to heparan sulphate proteoglycans (HSPGs). Protamine did not affect clearance rate, indicating that RAP-sensitive clearance of CCN-2 is HSPG independent. In conclusion, unlike its amino-terminal fragment which is cleared by the kidney, full length CCN-2 is primarily eliminated by the liver via a fast RAP-sensitive, probably LRP1-dependent pathway. | en_GB |
dc.description.sponsorship | FibroGen, Inc. | en_GB |
dc.identifier.citation | Vol. 10, pp. 295 - 303 | en_GB |
dc.identifier.doi | 10.1007/s12079-016-0354-6 | |
dc.identifier.uri | http://hdl.handle.net/10871/34982 | |
dc.language.iso | en | en_GB |
dc.publisher | Springer for International CCN Society (ICCNS) | en_GB |
dc.rights | © The Author(s) 2016. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. | en_GB |
dc.subject | Biomarker | en_GB |
dc.subject | CCN-2 | en_GB |
dc.subject | CTGF | en_GB |
dc.subject | Hepatic clearance | en_GB |
dc.subject | LRP1 | en_GB |
dc.title | Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2018-12-04T11:45:08Z | |
dc.identifier.issn | 1873-9601 | |
dc.description | This is the final version. Available on open access from Springer via the DOI in this record. | en_GB |
dc.identifier.journal | Journal of Cell Communication and Signaling | en_GB |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2016-09-08 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2016-09-19 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2018-12-04T11:43:31Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2018-12-04T11:45:10Z | |
refterms.panel | A | en_GB |
refterms.depositException | publishedGoldOA |
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