Journal Article

Human RAGE antibody protects against AGE-mediated podocyte dysfunction

Sandra Müller-Krebs, Lars P. Kihm, Thati Madhusudhan, Berend Isermann, Jochen Reiser, Martin Zeier and Vedat Schwenger

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 27, issue 8, pages 3129-3136
Published in print August 2012 | ISSN: 0931-0509
Published online April 2012 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfs005
Human RAGE antibody protects against AGE-mediated podocyte dysfunction

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Background

Residual renal function (RRF) contributes to better patient survival in peritoneal dialysis (PD). It is known that glucose degradation products (GDP) and advanced glycation end-products (AGE) resorbed from the peritoneal cavity do not only cause local peritoneal toxicity but also systemic damage resulting in a loss of RRF. We hypothesize that GDP and AGE affect the structure and function of podocytes and investigate whether these effects can be rescued by human RAGE antibody (hRAGEab) to prevent AGE/RAGE interaction and podocyte damage.

Methods

Differentiated human podocytes were pre-incubated with ±hRAGEab to block the AGE/RAGE interaction and incubated afterwards either with control solution (control), PD fluid (PDF) or a GDP mixture (GDP) for 48 h. We analysed podocyte damage and rescue by hRAGEab using immunofluorescence, western blot, enzyme-linked immunosorbent assay and a functional migration assay. For quantitation, a semiquantitative score was used.

Results

When pre-incubating podocytes with hRAGEab, damage mediated by PDF and GDP was reduced. We observed lower expression of AGE in PDF and GDP as well as decreased levels of inflammation as shown by activation of nuclear factor kappa B and interleukin-6 release. The reorganization of the podocyte actin cytoskeleton was reduced in the presence of hRAGEab as well as ameliorated synaptopodin expression could be observed, both functionally associated with normal podocyte motility. Finally, podocytes underwent less apoptosis.

Conclusions

It has been investigated that GDP-containing PDF causes a loss of RRF in PD. Our findings suggest that hRAGEab confers protection against PDF- and GDP-induced podocyte dysfunction. Blocking the AGE/RAGE interaction provides specific protective effects against PDF- and GDP-induced cytoskeletal reorganization, dynamics and stabilizes podocyte survival; this might be an implication for the preservation of RRF in PD.

Keywords: advanced glycation end-products; glucose degradation products; peritoneal dialysis fluids; podocytes; receptor for advanced glycation end-products

Journal Article.  3595 words.  Illustrated.

Subjects: Nephrology

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