Molecular and Functional Characterization of the Peritoneal Mesothelium, a Barrier for Solute Transport
Peritoneal dialysis (PD) is an increasingly needed, life-maintaining kidney replacement therapy; efficient solute transport is critical for patient outcome. While the role of peritoneal perfusion on solute transport in PD has been described, the role of cellular barriers is uncertain, the mesothelium has been considered irrelevant. We calculated peritoneal blood microvascular endothelial surface area (BESA) to mesothelial surface area (MSA) ratio in human peritonea in health, chronic kidney disease, and on PD, and performed molecular transport related gene profiling and single molecule localization microscopy in two mesothelial (MC) and two endothelial cell lines (EC). Molecular-weight dependent transport was studied in-vitro, ex-vivo and in mice. Peritoneal BESA is 1-3-fold higher than MSA across age groups, and increases with PD, while the mesothelium is preserved during the first 2 years of PD. Tight junction, transmembrane and transcytotic transporter expression are cell-type specifically expressed. At nanoscale, tight junction anchoring protein Zonula occludens-1 is more abundant and more continuously expressed along the MC than the EC. Ionic conductance is 3-fold lower across the MC than human microvascular EC, as is the permeability for creatinine, 4- and 10-kDa, but not for 70-kDa dextran. MC removal from sheep peritoneum abolishes ionic barrier function. Short term intraperitoneal LPS exposure in mice selectively affects peritoneal mesothelial integrity and increases transperitoneal solute transport. We provide molecular correlates and consistent functional evidence for the mesothelium as a barrier for peritoneal solute transport, ie, essential information on peritoneal transport modeling, and for interventions to improve PD efficiency and biocompatibility, and beyond.
Authors
- Domonkos Pap
- Sotirios I. Sinis (ORCID: https://orcid.org/0000-0003-3653-260X)
- Arslan Saleem Chughtai (ORCID: https://orcid.org/0000-0003-2746-4115)
- Maria Bartosova (ORCID: https://orcid.org/0000-0003-1127-3453)
- Trim Lajqi (ORCID: https://orcid.org/0000-0002-2584-589X)
- Klaus Kratochwill (ORCID: https://orcid.org/0000-0003-0803-614X)
- Susanne M. Krug (ORCID: https://orcid.org/0000-0002-1293-2484)
- Damir Krunic (ORCID: https://orcid.org/0000-0002-5615-627X)
- Claus Peter Schmitt (ORCID: https://orcid.org/0000-0003-4487-3332)
- Rebecca Herzog (ORCID: https://orcid.org/0000-0003-1946-7770)
- Iva Marinović (ORCID: https://orcid.org/0000-0003-0418-2561)
- Conghui Zhang (ORCID: https://orcid.org/0000-0003-4296-4054)
- József Szabó (ORCID: https://orcid.org/0000-0002-0082-6262)
- Ivan Damgov (ORCID: https://orcid.org/0000-0003-1482-7845)
- Juan Manuel Sacnun (ORCID: https://orcid.org/0000-0003-2394-8817)
- Eszter Lévai (ORCID: https://orcid.org/0000-0002-6149-3254)
- Sotirios G. Zarogiannis (ORCID: https://orcid.org/0000-0002-3083-3244)
- Eleanna Pitaraki (ORCID: https://orcid.org/0000-0002-6891-1041)
- Michael Hausmann (ORCID: https://orcid.org/0000-0001-9430-1987)
- Zhiwei Du
- Mohammed Al‐Saeedi (ORCID: https://orcid.org/0000-0002-0583-4472)
Institutions
- Semmelweis University (HU)
- University of Thessaly (GR)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Humboldt-Universität zu Berlin (DE)
- Comprehensive Cancer Center Vienna (AT)
- Kirchhoff (Germany) (DE)
- Medical University of Vienna (AT)
- Charité - Universitätsmedizin Berlin (DE)
- Heidelberg University (US)
Publication Details
- Journal
- Function
- Published
- 2024-12-06
- DOI
- https://doi.org/10.1093/function/zqae051
- Citations
- 2
- Primary Topic
- Dialysis and Renal Disease Management
- Type
- article
- Field-Weighted Citation Impact
- 0.68
Funders
- Österreichische Nationalstiftung für Forschung, Technologie und Entwicklung
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Wissenschaft, Forschung und Wirtschaft
- Magyar Tudományos Akadémia
- China Scholarship Council