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

Carolin Lepa; Sascha Hoppe; Antje Stöber; Boris V. Skryabin; Laura Katharina Sievers; Barbara Heitplatz; Giuliano Ciarimboli; Ute Neugebauer; Maja T. Lindenmeyer; Clemens D. Cohen; Hannes C.A. Drexler; Peter Boor; Thomas Weide; Hermann Pavenstädt; Britta George

doi:10.1681/ASN.2020040424

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Significance Statement

Identifying signaling pathways necessary for healthy glomeruli and nephrons could inform development of targeted therapies for glomerular diseases, which are largely lacking. Neurotrophic tyrosine kinase receptor 3 (TrkC) activity during nephron development and maintenance is part of one such pathway. Mice with deficiency or heterozygous or homozygous overexpression of TrkC in the nephron exhibit an expression level–dependent phenotype concomitant with albuminuria, podocyte foot process effacement, mesangial hypertrophy, and aspects of FSGS. In podocyte culture, activation of TrkC by its specific ligand results in transactivation of the Igf1 receptor (Igf1R), linking TrkC signal transduction to Igf-related signaling. These data identify TrkC as essential for maintaining glomerular integrity and to crosstalk with Igf-related signal transduction.

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.

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