Knock‐out of dipeptidase CN2 in human proximal tubular cells disrupts dipeptide and amino acid homeostasis and para‐ and transcellular solute transport

Author:

Pfeffer Tilman12ORCID,Krug Susanne M.3ORCID,Kracke Tamara1,Schürfeld Robin1,Colbatzky Florian1,Kirschner Philip1ORCID,Medert Rebekka4,Freichel Marc4,Schumacher Dagmar4,Bartosova Maria1,Zarogiannis Sotiris G.1,Muckenthaler Martina U.5678,Altamura Sandro56,Pezer Silvia1,Volk Nadine9,Schwab Constantin10,Duensing Stefan11,Fleming Thomas12,Heidenreich Elena13,Zschocke Johannes14,Hell Rüdiger13,Poschet Gernot13,Schmitt Claus P.1,Peters Verena1ORCID

Affiliation:

1. Medical Faculty Heidelberg, Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine Heidelberg University Heidelberg Germany

2. Tissue Bank of the German Center for Infection Research (DZIF), Partner Site Heidelberg, Institute of Pathology Heidelberg University Hospital Heidelberg Germany

3. Clinical Physiology/Nutritional Medicine Charité‐Universitätsmedizin Berlin, CBF Berlin Germany

4. Institute of Pharmacology Heidelberg University Heidelberg Germany

5. Department of Pediatric Oncology, Hematology and Immunology and Hopp Children Cancer Center (KiTZ) University Hospital Heidelberg Heidelberg Germany

6. Molecular Medicine Partnership Unit (MMPU) EMBL and University of Heidelberg Heidelberg Germany

7. Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL) University of Heidelberg Heidelberg Germany

8. DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim Heidelberg Germany

9. Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg Germany

10. Institute of Pathology University Hospital Heidelberg Heidelberg Germany

11. Department of Urology University Hospital Heidelberg and National Center for Tumor Diseases (NCT) Heidelberg Heidelberg Germany

12. Internal Medicine I and Clinical Chemistry University Hospital Heidelberg Heidelberg Germany

13. Centre for Organismal Studies (COS) University of Heidelberg Heidelberg Germany

14. Institute of Human Genetics Medical University of Innsbruck Innsbruck Austria

Abstract

AbstractAimAlthough 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.MethodsA 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.ResultsCNDP2‐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.ConclusionCN2 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.

Funder

Deutsche Forschungsgemeinschaft

Publisher

Wiley

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