TrkC Is Essential for Nephron Function and Trans-Activates Igf1R Signaling

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 recept...

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Published in:	Journal of the American Society of Nephrology 2021-02, Vol.32 (2), p.357-374
Main Authors:	Lepa, Carolin, Hoppe, Sascha, Stöber, Antje, Skryabin, Boris V, Sievers, Laura Katharina, Heitplatz, Barbara, Ciarimboli, Giuliano, Neugebauer, Ute, Lindenmeyer, Maja T, Cohen, Clemens D, Drexler, Hannes C A, Boor, Peter, Weide, Thomas, Pavenstädt, Hermann, George, Britta
Format:	Article
Language:	eng
Subjects:	Animals Basic Research Case-Control Studies Disease Models, Animal Humans Kidney Diseases - etiology Kidney Diseases - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Nephrons - metabolism Phosphoproteins - metabolism Podocytes - metabolism Receptor, IGF Type 1 - metabolism Receptor, trkC - metabolism Signal Transduction - physiology
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Summary:	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 ( ) is expressed in podocytes and the protein transmits signals to the podocyte actin cytoskeleton. Nephron-specific knockout ( ) and nephron-specific -overexpressing ( ) mice were generated to dissect the role of in nephron development and maintenance. Both and 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 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 mouse kidneys while it was decreased in kidneys. Furthermore, expression was elevated in glomerular tissue of patients with diabetic kidney disease compared with control glomerular tissue. Our results show that is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.
ISSN:	1046-6673 1533-3450