Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Hagmann, Henning UNSPECIFIED UNSPECIFIED UNSPECIFIED Khayyat, Naghmeh Hassanzadeh UNSPECIFIED UNSPECIFIED UNSPECIFIED Oezel, Cem UNSPECIFIED UNSPECIFIED UNSPECIFIED Papadakis, Antonios UNSPECIFIED orcid.org/0000-0002-2416-6772 UNSPECIFIED Kuczkowski, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED orcid.org/0000-0003-0512-1066 UNSPECIFIED Gulbins, Erich UNSPECIFIED UNSPECIFIED UNSPECIFIED Dryer, Stuart UNSPECIFIED UNSPECIFIED UNSPECIFIED Brinkkoetter, Paul T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language OXIDATIVE STRESS; SLIT DIAPHRAGM; PODOCYTES ROLE; CHANNELS; ACTIVATION; PODOCIN; PROTEIN; PLASMA; NEPHROPATHY; CHOLESTEROL Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67961