Hagmann, Henning, Khayyat, Naghmeh Hassanzadeh, Oezel, Cem, Papadakis, Antonios ORCID: 0000-0002-2416-6772, Kuczkowski, Alexander, Benzing, Thomas ORCID: 0000-0003-0512-1066, Gulbins, Erich, Dryer, Stuart and Brinkkoetter, Paul T. (2022). Paraoxonase 2 (PON2) Deficiency Reproduces Lipid Alterations of Diabetic and Inflammatory Glomerular Disease and Affects TRPC6 Signaling. Cells, 11 (22). BASEL: MDPI. ISSN 2073-4409

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Abstract

Diabetes and inflammatory diseases are associated with an altered cellular lipid composition due to lipid peroxidation. The pathogenic potential of these lipid alterations in glomerular kidney diseases remains largely obscure as suitable cell culture and animal models are lacking. In glomerular disease, a loss of terminally differentiated glomerular epithelial cells called podocytes refers to irreversible damage. Podocytes are characterized by a complex ramified cellular architecture and highly active transmembrane signaling. Alterations in lipid composition in states of disease have been described in podocytes but the pathophysiologic mechanisms mediating podocyte damage are unclear. In this study, we employ a genetic deletion of the anti-oxidative, lipid-modifying paraoxonase 2 enzyme (PON2) as a model to study altered cellular lipid composition and its effects on cellular signaling in glomerular disease. PON2 deficiency reproduces features of an altered lipid composition of glomerular disease, characterized by an increase in ceramides and cholesterol. PON2 knockout mice are more susceptible to glomerular damage in models of aggravated oxidative stress such as adriamycin-induced nephropathy. Voltage clamp experiments in cultured podocytes reveal a largely increased TRPC6 conductance after a membrane stretch in PON2 deficiency. Correspondingly, a concomitant knockout of TRPC6 and PON2 partially rescues the aggravated glomerular phenotype of a PON2 knockout in the adriamycin model. This study establishes PON2 deficiency as a model to investigate the pathophysiologic mechanisms of podocyte dysfunction related to alterations in the lipid composition, as seen in diabetic and inflammatory glomerular disease. Expanding the knowledge on these routes and options of intervention could lead to novel treatment strategies for glomerular disease.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hagmann, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khayyat, Naghmeh HassanzadehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oezel, CemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papadakis, AntoniosUNSPECIFIEDorcid.org/0000-0002-2416-6772UNSPECIFIED
Kuczkowski, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benzing, ThomasUNSPECIFIEDorcid.org/0000-0003-0512-1066UNSPECIFIED
Gulbins, ErichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dryer, StuartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkkoetter, Paul T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-679610
DOI: 10.3390/cells11223625
Journal or Publication Title: Cells
Volume: 11
Number: 22
Date: 2022
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2073-4409
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
OXIDATIVE STRESS; SLIT DIAPHRAGM; PODOCYTES ROLE; CHANNELS; ACTIVATION; PODOCIN; PROTEIN; PLASMA; NEPHROPATHY; CHOLESTEROLMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/67961

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