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Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids and its modification by Stearoyl-CoA desaturases and cyclic AMP

Sieber, Jonas. Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids and its modification by Stearoyl-CoA desaturases and cyclic AMP. 2011, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_9785

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Abstract

Podocyte apoptosis is a hallmark in the development and progression of diabetic nephropathy (DN). Several factors of the diabetic milieu are known to induce podocyte apoptosis. Currently, the role of free fatty acids (FFAs) for podocytopathy and podocyte cell death is unknown, although FFAs are considered to be crucially involved in the development of diabetes mellitus type II. It is well known that FFAs are toxic to several cell types including pancreatic § cells and they may contribute to the development of insulin resistance. The aims of this study were to elucidate the role of the saturated palmitic acid and the monounsaturated palmitoleic and oleic acid on podocyte cell death and endoplasmic reticulum (ER)-stress, to investigate more specifically the impact of ER-stress on podocyte survival as well as to elaborate strategies to protect podocytes from lipotoxicity.
The present study uncovered that palmitic acid induces podocyte apoptosis and necrosis and leads to ER-stress as reflected by induction of the unfolded protein response (UPR), i.e. upregulation of the ER chaperone immunoglobulin heavy chain binding protein (BiP), X-box protein 1 (XBP-1) mRNA splicing, and a strong upregulation of the proapoptotic transcription factor C/EBP homologous protein (CHOP). Gene silencing experiments of CHOP support a crucial involvment of CHOP and ER-stress in mediating the proapoptotic effect of palmitic acid in podocytes. Contrariwise, monounsaturated FFAs (MUFAs) such as palmitoleic and oleic acid prevent palmitic acid-induced podocyte death and attenuate ER-stress.
This study further revealed that the liver X receptor (LXR) agonist TO901317 (TO) ameliorates survival of palmitic acid-treated podocytes. Mechanistically, this beneficial effect can be explained mainly by the induction of stearoyl-CoA desaturase (SCD-) 1 and 2 as shown by gene silencing experiments and further supported from overexpression studies of SCD-1. Moreover, palmitic acid tracing experiments revealed a higher incorporation of palmitic acid into the triglyceride (TG) fraction in podocytes treated with TO or oleic acid, which is at least compatible with a benefit of increased fatty acid storage, by TO, i.e. SCDs, and MUFAs, respectively.
In addition, this study provides some preliminary data that adenylate cyclases (AC) may be an interesting target to protect podocytes from ER-stress in general and in particular from palmitic acid-induced podocytopathy and cell death. Experiments with forskolin, a specific AC agonist, and cyclic AMP (cAMP) analogons protect from palmitic acid-induced podocyte lipotoxicity. The effect cannot be explained by an involvment of PKA-CREB signaling as overexpression of a dominant negative CREB mutant could not abrogate the protective effect of forskolin. Furthermore, the beneficial impact of forskolin is not influencing the intrinisic (mitochondrial) apoptotic pathway. However, in addition to the protection from palmitic acid-induced cell death, forskolin is suppressing podocyte death caused by other independent ER-stressors such as tunicamycin and thapsigargin. These findings suggest a direct role of forskolin and increased cAMP levels for a protection from ER-stress in podocytes.
In summary, this study unveiled antagonistic effects of palmitic acid versus monounsaturated FFAs for podocyte survival, ER-stress and the UPR. They support an important role of CHOP in the regulation of podocyte death by FFAs. Similarly to exogenous MUFAs, induction of SCDs partially protects podocytes from palmitic acid-induced ER-stress and podocyte death. The protective effect of MUFAs may be related to increased incorporation of palmitic acid into TGs. Additional, preliminary data indicate that AC agonists such as forskolin may be interesting compounds to protect podocytes from ER-stress and from the toxic effects of FFAs. The results of this study offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance toward MUFAs, or tissue- (podocyte-) specific stimulation or overexpression of SCDs can delay the progression of DN. Similarly, the results of this study should encourage more studies to evaluate the therapeutic potential of AC agonists or phosphodiesterase inhibitors for the prevention and treatment of DN.
Advisors:Palmer, Ed
Committee Members:Donath, Marc and Jehle, Andreas
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Nephrologie > Exp. Transplantationsimmunologie und Nephrologie (Palmer)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Nephrologie > Exp. Transplantationsimmunologie und Nephrologie (Palmer)
Item Type:Thesis
Thesis no:9785
Bibsysno:Link to catalogue
Number of Pages:1 Bd.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:42
Deposited On:28 Feb 2012 14:51

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