Severe ischemia-reperfusion injury induces epigenetic inactivation of LHX1 in kidney progenitor cells after kidney transplantation
Severe ischemia-reperfusion injury (IRI) causes acute and chronic kidney allograft damage. As therapeutic interventions to reduce damage are limited yet, research on how to promote kidney repair has gained significant interest. To address this question, we performed genome-wide transcriptome and epigenome profiling in progenitor cells isolated from the urine of deceased (severe IRI) and living (mild IRI) donor human kidney transplants and identified LIM homeobox-1 (LHX1) as an epigenetically regulated gene whose expression depends on the IRI severity. Using a mouse model of IRI, we observed a relationship between IRI severity, LHX1 promoter hypermethylation, and LHX1 gene expression. Using functional studies, we confirmed that LHX1 expression is involved in the proliferation of epithelial tubular cells and podocyte differentiation from kidney progenitor cells. Our results provide evidence that severe IRI may reduce intrinsic mechanisms of kidney repair through epigenetic signaling.
Authors
- Cristián Varela (ORCID: https://orcid.org/0000-0002-4494-5810)
- Montserrat Gomà‐i‐Freixanet (ORCID: https://orcid.org/0000-0003-3146-1750)
- Angelika Merkel (ORCID: https://orcid.org/0000-0001-5164-6803)
- Miguel L. Pato (ORCID: https://orcid.org/0000-0001-8840-7259)
- Francesc Vigués (ORCID: https://orcid.org/0000-0003-3717-6301)
- Núria Garcia Doladé
- Fernando Setién (ORCID: https://orcid.org/0000-0002-4061-4635)
- Paola Romagnani (ORCID: https://orcid.org/0000-0002-1774-8088)
- Josep M. Cruzado (ORCID: https://orcid.org/0000-0003-1388-8558)
- James S. Heald
- María Berdasco (ORCID: https://orcid.org/0000-0002-6750-0400)
- Anna Manonelles (ORCID: https://orcid.org/0000-0003-2456-388X)
- Ana Amaya-Garrido (ORCID: https://orcid.org/0009-0008-6037-2638)
- David Piñeyro (ORCID: https://orcid.org/0000-0001-5633-3339)
- Carlos Couceiro (ORCID: https://orcid.org/0000-0002-8303-8703)
- Anna Solà (ORCID: https://orcid.org/0000-0003-2379-9313)
- Núria Bolaños (ORCID: https://orcid.org/0009-0009-1525-8542)
- Sergi Codina (ORCID: https://orcid.org/0000-0002-2313-6109)
- Carlos Quero-Dotor
Institutions
- Bellvitge University Hospital (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- Meyer Children's Hospital (IT)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
Publication Details
- Journal
- American Journal of Transplantation
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1016/j.ajt.2024.11.003
- Citations
- 1
- Primary Topic
- Renal and related cancers
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- Centres de Recerca de Catalunya
- Generalitat de Catalunya
- Instituto de Salud Carlos III
- European Regional Development Fund