TrkC Is Essential for Nephron Function and Trans-Activates Igf1R Signaling
Journal of the American Society of Nephrology, vol. 32, pp. 357–374
Abstract
Background Injury to kidney podocytes often results in chronic glomerular disease and consecutive nephron malfunction. For most glomerular diseases, targeted therapies are lacking. Thus, it is important to identify novel signaling pathways contributing to glomerular disease. Neurotrophic tyrosine kinase receptor 3 ( TrkC ) is expressed in podocytes and the protein transmits signals to the podocyte actin cytoskeleton. Methods Nephron-specific TrkC knockout ( TrkC-KO ) and nephron-specific TrkC -overexpressing ( TrkC-OE ) mice were generated to dissect the role of TrkC in nephron development and maintenance. Results Both TrkC-KO and TrkC-OE mice exhibited enlarged glomeruli, mesangial proliferation, basement membrane thickening, albuminuria, podocyte loss, and aspects of FSGS during aging. Igf1 receptor (Igf1R)–associated gene expression was dysregulated in TrkC-KO mouse glomeruli. Phosphoproteins associated with insulin, erb-b2 receptor tyrosine kinase (Erbb), and Toll-like receptor signaling were enriched in lysates of podocytes treated with the TrkC ligand neurotrophin-3 (Nt-3). Activation of TrkC by Nt-3 resulted in phosphorylation of the Igf1R on activating tyrosine residues in podocytes. Igf1R phosphorylation was increased in TrkC-OE mouse kidneys while it was decreased in TrkC-KO kidneys. Furthermore, TrkC expression was elevated in glomerular tissue of patients with diabetic kidney disease compared with control glomerular tissue. Conclusions Our results show that TrkC is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.
Authors 14
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Affiliation as printed
Medizinische Klinik D, University Hospital Münster, Münster, Germany
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Affiliation as printed
Medizinische Klinik D, University Hospital Münster, Münster, Germany
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Affiliation as printed
Medizinische Klinik D, University Hospital Münster, Münster, Germany
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Affiliation as printed
Medical Faculty, Core Facility Transgenic Animal and Genetic Engineering Models (TRAM), Westfälische-Wilhelms-University, Münster, Germany
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Affiliation as printed
Medizinische Klinik D, University Hospital Münster, Münster, Germany
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Affiliation as printed
Gerhard-Domagk Institute for Pathology, University Hospital Münster, Münster, Germany
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Affiliation as printed
Medizinische Klinik D, University Hospital Münster, Münster, Germany
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University Medical Center Hamburg-Eppendorf
Affiliation as printed
III. Medizinische Klinik und Poliklinik, University Hospital Hamburg-Eppendorf, Germany
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Affiliation as printed
Klinik für Nieren-, Hochdruck- und Rheumaerkrankungen, München Klinik Harlaching, Germany
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Max Planck Institute for Molecular Biomedicine
Affiliation as printed
Mass Spectrometry Unit, Max Planck Institute for Molecular Biomedicine, Münster, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Pathology and Department of Nephrology, University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
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Affiliation as printed
Medizinische Klinik D, University Hospital Münster, Münster, Germany
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Affiliation as printed
Medizinische Klinik D, University Hospital Münster, Münster, Germany
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Affiliation as printed
Medizinische Klinik D, University Hospital Münster, Münster, Germany
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