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

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

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.

View Full Text

If you are:

an ASN member, select the "ASN Member" login button.
an individual subscriber, login with you User Name and Password.
an Institutional user, select the Institution option where you will be presented with a list of Shibboleth federations. If you do not see your federation, contact publications@asn-online.org.

Log in through your institution

Purchase access

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$32.00

In order to get access to the article, you must have an account. If you have an account, enter your user name and password into the boxes above. If you do not have an account, follow the instructions below to create one. Once you have purchased the article, you will have access to it for 24 hours.

Steps for Creating an Account:

Click the "Purchase Access" button. The page will redisplay with the following message at the top of the screen. In the message, click to create an account.

When you create the account, you will be asked to register a user name, email address and you will need to create a password that is at least eight characters in length. You do not need an ASN Member number to complete the form. As you move through the registration page, you will have to verify you are a person by completing a Captcha request. Lastly, your first and last name will be required.

Once your information is successfully saved, the system will redisplay the home page of the journal. From there, navigate back to the article to purchase. Select the article and at the bottom of the page, use the credentials you just created to login. The article will be added to your shopping cart. You can continue to navigate across JASN and CJASN adding to your cart from both journals. When you are ready to complete your purchse, select the Shopping Cart from the upper right hand corner of the page and follow the onscreen instructions.