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Fetuin A exacerbates palmitic acid induced podocyte death and can be attenuated by antagonizing Il-1β

Orellana, Jana M.. Fetuin A exacerbates palmitic acid induced podocyte death and can be attenuated by antagonizing Il-1β. 2016, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12398

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Abstract

Diabetic nephropathy (DN) has become a leading cause of end stage renal
disease (ESRD) in industrialized countries, and most affected patients have
type 2 diabetes (T2D). Over the last years it has become evident that sterile
inflammation plays a central role in the pathogenesis of DN. Accumulation of
macrophages was demonstrated in humans and rodent models of DN, and
inhibition of inflammatory cell recruitment into the kidney was shown to be
protective in experimental DN. In addition to immune cells, intrinsic renal
cells, such as podocytes and mesangial cells, can also secrete pro-inflammatory cytokines, which may contribute to the inflammatory processand aggravate DN.
The aim of the present study was to investigate whether palmitic acid,
Fetuin-A or their combination elicit an inflammatory response involving toll-
like receptor 4 (TLR4) in podocytes and whether this inflammatory pathway
affects podocyte survival. Further, I aimed to investigate whether interleukin-
1β (IL-1β) signaling can modulate podocyte death. Finally, I performed a pilot
study in diabetic mice to investigate whether inhibition of IL-1β with a
murinized anti-IL-1β antibody may attenuate albuminuria and/or surrogate
markers of DN.
The present study uncovered that Fetuin-A or LPS exacerbate palmitic acid
induced podocyte death, which is associated with a strong inflammatory
response as indicated by the induction of monocyte chemoattractant protein-
1 (MCP-1) and keratinocyte chemoattractant (KC). Moreover, blockage of
TLR4 dramatically decreased MCP-1 and KC secretion and attenuated
podocyte death induced by palmitic acid alone and/or Fetuin-A in
combination with palmitic acid.
In addition, inhibition of IL-1 signaling by anakinra, a recombinant human IL-1Ra, or a murinized anti-IL-1β antibody attenuated the inflammatory response elicited by Fetuin-A and palmitic acid and -similar to TLR4-inhibition- attenuated podocyte death.In vivo, therapy of diabetic DBA/2J mice with an anti-IL-1β antibodyprevented an increase in serum Fetuin-A concentrations and considerablydecreased tumor necrosis factor alpha (TNF-alpha) secretion in the urine, which is thought to correlate reciprocally with DN progression. In the short term, however, therapy with the anti-IL-1β antibody was not able to protect from albuminuria.
In summary, the results suggest that Fetuin-A leads to an inflammatory
response in podocytes which exacerbates palmitic acid induced podocyte
death. The data suggest also that TLR4 signaling plays a role as a modulator
in the initiation and perturbation of the inflammatory process and leads to an
exacerbation of palmitic acid induced podocyte death. In addition, this study
implies a critical role for IL-1β signaling in palmitic acid induced podocyte
death. In vivo, therapy of diabetic mice with an anti-IL-1β antibody favorably
affected Fetuin-A levels in serum and urinary TNFα-levels, but in the short
term a beneficial effect on albuminuria was absent, which gives the rational
for prolonged studies to further test this new therapeutic approach.
Advisors:Palmer, Ed and Donath, Marc and Jehle, Andreas
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Transplantation Immunology and Nephrology (Palmer/Steiger)
UniBasel Contributors:Palmer, Ed and Donath, Marc
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12398
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (VIII, 40 Blätter)
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:53
Deposited On:27 Nov 2017 14:27

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