Phosphorylation of S6RP in peritubular capillaries of kidney grafts and circulating HLA donor-specific antibodies

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• dc.contributor.author Raïch-Regué, Dàlia
• dc.contributor.author Gimeno, Javier
• dc.contributor.author Llinàs-Mallol, Laura
• dc.contributor.author Menéndez, Silvia
• dc.contributor.author Benito, David
• dc.contributor.author Redondo, Dolores
• dc.contributor.author Pérez-Sáez, María José
• dc.contributor.author Riera, Marta
• dc.contributor.author Reed, Elaine F.
• dc.contributor.author Pascual Santos, Julio
• dc.contributor.author Crespo Barrio, Marta
• dc.date.accessioned 2023-04-04T06:02:29Z
• dc.date.available 2023-04-04T06:02:29Z
• dc.date.issued 2022
• dc.description.abstract Antibody-mediated rejection (ABMR) caused by donor-specific HLA-antibodies (DSA) is a mediator of allograft loss after kidney transplantation (KT). DSA can activate microvascular endothelium damage through the mTOR pathway. In this study we assessed the mTOR pathway activation by DSA in KT with ABMR (ABMR + DSA+) compared to controls (ABMR-DSA-), biopsies with ABMR changes without DSA (ABMR + DSA-) and DSA without ABMR changes (ABMR-DSA+), and the potential modulation by mTOR inhibitors (mTORi). We evaluated 97 biopsies: 31 ABMR + DSA+, 33 controls ABMR-DSA-, 16 ABMR + DSA-, and 17 ABMR-DSA+ cases. Regarding immunosuppression of full ABMR + DSA+ and controls, 21 biopsies were performed under mTORi treatment (11 of them ABMR + DSA+ cases) and 43 without mTORi (20 of them ABMR + DSA+) so as to explore its effect on the mTOR pathway. Biopsies were stained for C4d, Ki67, and phosphorylated (p) S6RP, ERK, and mTOR by immunohistochemistry. Labeling was graded according to peritubular capillary staining. ABMR biopsies showed significantly higher C4d, p-S6RP, and Ki67 staining in peritubular capillaries (PTC) compared to controls, and light differences in p-ERK or p-mTOR. mTORi treatment did not modify p-S6RP, p-mTOR, and p-ERK staining. Diffuse p-S6RP in PTC in the biopsies significantly associated with circulating HLA-DSA independently of graft rejection, and with worse death-censored graft survival. These findings suggest that activation of endothelium through the mTOR pathway evidence different mechanisms of damage in ABMR + DSA+ and ABMR + DSA- despite similar histological injury.
• dc.format.mimetype application/pdf
• dc.identifier.citation Raïch-Regué D, Gimeno J, Llinàs-Mallol L, Menéndez S, Benito D, Redondo D, Pérez-Sáez MJ, Riera M, Reed EF, Pascual J, Crespo M. Phosphorylation of S6RP in peritubular capillaries of kidney grafts and circulating HLA donor-specific antibodies. Front Med (Lausanne). 2022 Oct 18;9:988080. DOI: 10.3389/fmed.2022.988080
• dc.identifier.doi http://dx.doi.org/10.3389/fmed.2022.988080
• dc.identifier.issn 2296-858X
• dc.identifier.uri http://hdl.handle.net/10230/56404
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.ispartof Front Med (Lausanne). 2022 Oct 18;9:988080
• dc.rights © 2022 Raïch-Regué, Gimeno, Llinàs-Mallol, Menéndez, Benito, Redondo, Pérez-Sáez, Riera, Reed, Pascual and Crespo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Antibody mediated allograft rejection
• dc.subject.keyword Donor specific antibodies
• dc.subject.keyword Mammalian target of rapamycin (mTOR)
• dc.subject.keyword Peritubular capillaries
• dc.subject.keyword Phosphorylation
• dc.subject.keyword Ribosomal protein S6 (S6RP)
• dc.subject.keyword Transplantation—kidney
• dc.title Phosphorylation of S6RP in peritubular capillaries of kidney grafts and circulating HLA donor-specific antibodies
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion