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Knock-out of dipeptidase CN2 in human proximal tubular cells disrupts dipeptide and amino acid homeostasis and para- and transcellular solute transport.
Pfeffer, Tilman; Krug, Susanne M; Kracke, Tamara; Schürfeld, Robin; Colbatzky, Florian; Kirschner, Philip; Medert, Rebekka; Freichel, Marc; Schumacher, Dagmar; Bartosova, Maria; Zarogiannis, Sotiris G; Muckenthaler, Martina U; Altamura, Sandro; Pezer, Silvia; Volk, Nadine; Schwab, Constantin; Duensing, Stefan; Fleming, Thomas; Heidenreich, Elena; Zschocke, Johannes; Hell, Rüdiger; Poschet, Gernot; Schmitt, Claus P; Peters, Verena.
Afiliación
  • Pfeffer T; Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Heidelberg, Germany.
  • Krug SM; Tissue Bank of the German Center for Infection Research (DZIF), Partner Site Heidelberg, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • Kracke T; Clinical Physiology/Nutritional Medicine, Charité-Universitätsmedizin Berlin, CBF, Berlin, Germany.
  • Schürfeld R; Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Heidelberg, Germany.
  • Colbatzky F; Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Heidelberg, Germany.
  • Kirschner P; Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Heidelberg, Germany.
  • Medert R; Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Heidelberg, Germany.
  • Freichel M; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
  • Schumacher D; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
  • Bartosova M; Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
  • Zarogiannis SG; Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Heidelberg, Germany.
  • Muckenthaler MU; Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Heidelberg, Germany.
  • Altamura S; Department of Pediatric Oncology, Hematology and Immunology and Hopp Children Cancer Center (KiTZ), University Hospital Heidelberg, Heidelberg, Germany.
  • Pezer S; Molecular Medicine Partnership Unit (MMPU), EMBL and University of Heidelberg, Heidelberg, Germany.
  • Volk N; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
  • Schwab C; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
  • Duensing S; Department of Pediatric Oncology, Hematology and Immunology and Hopp Children Cancer Center (KiTZ), University Hospital Heidelberg, Heidelberg, Germany.
  • Fleming T; Molecular Medicine Partnership Unit (MMPU), EMBL and University of Heidelberg, Heidelberg, Germany.
  • Heidenreich E; Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University, Heidelberg, Germany.
  • Zschocke J; Tissue Bank of the National Center for Tumor Diseases (NCT), Heidelberg, Germany.
  • Hell R; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
  • Poschet G; Department of Urology, University Hospital Heidelberg and National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany.
  • Schmitt CP; Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany.
  • Peters V; Centre for Organismal Studies (COS), University of Heidelberg, Heidelberg, Germany.
Acta Physiol (Oxf) ; 240(4): e14126, 2024 04.
Article en En | MEDLINE | ID: mdl-38517248
ABSTRACT

AIM:

Although of potential biomedical relevance, dipeptide metabolism has hardly been studied. We found the dipeptidase carnosinase-2 (CN2) to be abundant in human proximal tubules, which regulate water and solute homeostasis. We therefore hypothesized, that CN2 has a key metabolic role, impacting proximal tubular transport function.

METHODS:

A knockout of the CN2 gene (CNDP2-KO) was generated in human proximal tubule cells and characterized by metabolomics, RNA-seq analysis, paracellular permeability analysis and ion transport.

RESULTS:

CNDP2-KO in human proximal tubule cells resulted in the accumulation of cellular dipeptides, reduction of amino acids and imbalance of related metabolic pathways, and of energy supply. RNA-seq analyses indicated altered protein metabolism and ion transport. Detailed functional studies demonstrated lower CNDP2-KO cell viability and proliferation, and altered ion and macromolecule transport via trans- and paracellular pathways. Regulatory and transport protein abundance was disturbed, either as a consequence of the metabolic imbalance or the resulting functional disequilibrium.

CONCLUSION:

CN2 function has a major impact on intracellular amino acid and dipeptide metabolism and is essential for key metabolic and regulatory functions of proximal tubular cells. These findings deserve in vivo analysis of the relevance of CN2 for nephron function and regulation of body homeostasis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dipeptidasas Límite: Humans Idioma: En Revista: Acta Physiol (Oxf) Asunto de la revista: FISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dipeptidasas Límite: Humans Idioma: En Revista: Acta Physiol (Oxf) Asunto de la revista: FISIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido