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Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids


Sieber, J; Lindenmeyer, M T; Kampe, K; Campbell, K N; Cohen, C D; Hopfer, H; Mundel, P; Jehle, A W (2010). Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids. American Journal of Physiology. Renal Physiology, 299(4):F821-F829.

Abstract

Apoptosis of podocytes is considered critical in the pathogenesis of diabetic nephropathy (DN). Free fatty acids (FFAs) are critically involved in the pathogenesis of diabetes mellitus type 2, in particular the regulation of pancreatic beta-cells survival. The objectives of this study were to elucidate the role of palmitic acid, palmitoleic, and oleic acid in the regulation of podocyte cell death and endoplasmic reticulum (ER) stress. We show that palmitic acid increases podocyte cell death, both apoptosis and necrosis of podocytes in a dose and time-dependent fashion. Palmitic acid induces podocyte ER stress leading to an unfolded protein response (UPR) as reflected by the induction of the ER chaperon immunoglobulin heavy chain binding protein (BiP) and proapoptotic C/EBP (CCAAT/enhancer binding protein) homologous protein (CHOP) transcription factor. Of note, the monounsaturated palmitoleic and oleic acid can attenuate the palmitic acid-induced upregulation of CHOP, thereby preventing cell death. Similarly, gene silencing of CHOP protects against palmitic acid induced podocyte apoptosis. Our results offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance towards unsaturated FFAs can delay the progression of DN.

Apoptosis of podocytes is considered critical in the pathogenesis of diabetic nephropathy (DN). Free fatty acids (FFAs) are critically involved in the pathogenesis of diabetes mellitus type 2, in particular the regulation of pancreatic beta-cells survival. The objectives of this study were to elucidate the role of palmitic acid, palmitoleic, and oleic acid in the regulation of podocyte cell death and endoplasmic reticulum (ER) stress. We show that palmitic acid increases podocyte cell death, both apoptosis and necrosis of podocytes in a dose and time-dependent fashion. Palmitic acid induces podocyte ER stress leading to an unfolded protein response (UPR) as reflected by the induction of the ER chaperon immunoglobulin heavy chain binding protein (BiP) and proapoptotic C/EBP (CCAAT/enhancer binding protein) homologous protein (CHOP) transcription factor. Of note, the monounsaturated palmitoleic and oleic acid can attenuate the palmitic acid-induced upregulation of CHOP, thereby preventing cell death. Similarly, gene silencing of CHOP protects against palmitic acid induced podocyte apoptosis. Our results offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance towards unsaturated FFAs can delay the progression of DN.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nephrology
04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2010
Deposited On:09 Aug 2010 11:50
Last Modified:05 Apr 2016 14:13
Publisher:American Physiological Society
ISSN:0363-6127
Publisher DOI:https://doi.org/10.1152/ajprenal.00196.2010
PubMed ID:20668104
Permanent URL: https://doi.org/10.5167/uzh-35308

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