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

Abstract

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 (<i>TrkC</i>) is expressed in podocytes and the protein transmits signals to the podocyte actin cytoskeleton. Nephron-specific <i>TrkC</i> knockout (<i>TrkC-KO</i>) and nephron-specific <i>TrkC</i>-overexpressing (<i>TrkC-OE</i>) mice were generated to dissect the role of <i>TrkC</i> in nephron development and maintenance. Both <i>TrkC-KO</i> and <i>TrkC-OE</i> 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 <i>TrkC-KO</i> 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 <i>TrkC-OE</i> mouse kidneys while it was decreased in <i>TrkC-KO</i> kidneys. Furthermore, <i>TrkC</i> expression was elevated in glomerular tissue of patients with diabetic kidney disease compared with control glomerular tissue. Our results show that <i>TrkC</i> is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.