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The receptor for advanced glycation end-products (RAGE) plays a key role in the formation of nanotubes (NTs) between peritoneal mesothelial cells and in murine kidneys

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Abstract

The receptor for advanced glycation end-products (RAGE), a multiligand receptor of the immunoglobulin superfamily, takes part in various inflammatory processes. The role of this receptor in the context of intercellular communication, like nanotube (NT)-mediated interaction, is largely unknown. Here, we use cell cultures of human and murine peritoneal mesothelial cells as well as murine kidneys from wild-type and RAGE knockout mouse models to assess the role of RAGE in NT formation and function. We show that loss of RAGE function results in reduced NT numbers under physiological conditions and demonstrate the involvement of MAP kinase signaling in NT formation. Additionally, we show for the first time the existence of NTs in murine kidney tissue and confirm the correlation of RAGE expression and NT numbers. Under elevated oxidative stress conditions like renal ischemia or peritoneal dialysis, we demonstrate that RAGE absence does not prevent NT formation. Rather, increased NT numbers and attenuated kidney tissue damage could be observed, indicating that, depending on the predominant conditions, RAGE affects NT formation with implications for cellular communication.

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Acknowledgments

We wish to thank Dr. Luis Becker and Simone Schmidt, both from the Department of Nephrology, as well as Annette Kohl from the Department of Orthodontics and Dentofacial Orthopaedics at the University of Heidelberg for technical assistance. Additional thanks goes to Dr. Arianeb Mehrabi from the Department of Surgery as well as to the Nikon Imaging Center, both at the University of Heidelberg, Germany.

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Authors and Affiliations

  1. Department of Nephrology, University of Heidelberg, Heidelberg, Germany

    Julia Ranzinger, Danijela Heide, Christian Morath, Martin Zeier & Vedat Schwenger

  2. Department of New Materials and Biosystems, Max Planck Institute for Intelligent Systems, Stuttgart and Department of Biophysical Chemistry, University of Heidelberg, Heidelberg, Germany

    Amin Rustom

  3. Department of Surgery, University of Heidelberg, Heidelberg, Germany

    Peter Schemmer

  4. Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany

    Peter P. Nawroth

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  1. Julia Ranzinger
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Correspondence to Julia Ranzinger.

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Supplementary Fig. 1

Characterization of patient-derived HPMCs. Brightfield and immunofluorescence microscopy of HPMCs isolated from portions of omentum from seven different donors. Cells were characterized by their cellular morphology (left panel) as well as by the expression of the mesothelial cell marker Cytokeratin 18 (central panel) and the fibroblast cell marker FSP (right panel). Cell nuclei were stained with Hoechst 33342. (GIF 458 kb)

High resolution image (TIFF 28097 kb)

Supplementary Fig. 2

Characterization of additive patient-derived HPMCs. Brightfield and immunofluorescence microscopy of HPMCs isolated from portions of omentum from three different donors. Cells were characterized by their cellular morphology (left panel) as well as by the expression of the mesothelial cell marker Cytokeratin 18, the fibroblast cell marker FSP and the mesenchymal cell marker Vimentin. Cell nuclei were stained with Hoechst 33342. (GIF 281 kb)

High resolution image (TIFF 17832 kb)

Supplementary Fig. 3

NT-formation between HPMCs is dependent on p38 activation. HPMCs were treated with proteasome inhibitor 1 h prior to stimulation with MG alone or in combination with a RAGE-blocking antibody (a, b). After 1 h of stimulation, cells were lysed and p-p38 (a, b) as well as total p38 protein expression (c, d) was assessed by western blot (e, f). For the investigation of NT numbers, HPMCs were treated with a p38 MAPK inhibitor (black bars) or left untreated (white bars) and NT numbers were analyzed 1 h after cell plating. Data are shown as means ± SEM, n = 3 for each donor. (GIF 69 kb)

High resolution image (TIFF 1989 kb)

Supplementary Fig. 4

Detection of apoptosis and necrosis in HPMCs after treatment with dialysis solution and TNX/CHX. Brightfield and immunofluorescence microscopy of HPMCs from Donor VIII (a), IX (b) and X (c) stained with FITC-Annexin V, Ethidium homodimer-III and Hoechst 33342 cultured in medium (upper panel), 1 h after incubation with dialysis solution (middle panel) and 6 h after treatment with TNF/CHX (lower panel). The graphs in (d) show that treatment of the cells with dialysis solution has no effect on apoptosis (upper graph) or necrosis (lower graph) compared to TNF/CHX treatment. (GIF 517 kb)

High resolution image (TIFF 30630 kb)

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Ranzinger, J., Rustom, A., Heide, D. et al. The receptor for advanced glycation end-products (RAGE) plays a key role in the formation of nanotubes (NTs) between peritoneal mesothelial cells and in murine kidneys. Cell Tissue Res 357, 667–679 (2014). https://doi.org/10.1007/s00441-014-1904-y

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