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

Abstract

BackgroundInjury 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.MethodsNephron-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.ResultsBoth 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.ConclusionsOur results show that TrkC is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.

Analysis of the Expression of Neurotrophins and Their Receptors in Adult Zebrafish Kidney

“…Our results, obtained by qPCR and ISH, show that nt3/trkC is the most expressed in different regions, including the hematopoietic cells, similarly to the mammalian kidney [62,63]. Previous observations in rats and humans highlighted that nt3 and trkC mRNA levels were elevated in the glomerular tissue, and this signaling could be involved in the regulation of renal tubule transport [64][65][66]. In detail, Lepa and colleagues, using a mammal animal model, confirmed that nephron-specific TrkC knockout (TrkC-KO) and TrkC-overexpressing (TrkC-OE) mice presented enlarged glomeruli with mesangial proliferation, podocyte loss during aging, basement membrane thickening, and albuminuria.…”

“…In detail, Lepa and colleagues, using a mammal animal model, confirmed that nephron-specific TrkC knockout (TrkC-KO) and TrkC-overexpressing (TrkC-OE) mice presented enlarged glomeruli with mesangial proliferation, podocyte loss during aging, basement membrane thickening, and albuminuria. They also showed that NT3-dependent TrkC activation in cultured podocytes and overexpression of TrkC in the nephron in mice lead to the phosphorylation of the activating tyrosine residues of the Igf1R [66].…”

Klotho inhibits IGF1R/PI3K/AKT signalling pathway and protects the heart from oxidative stress during ischemia/reperfusion injury

“…The level of PI3K correlated with phosphorylation of IGF1R, which con rms activation of the pathway during IRI. It was shown that dysregulation of IGF signalling played a role in several kidney diseases, such as proteinuric CKD and polycystic kidneys [24]. Downregulating the IGF1R/PI3K pathway limited loss of podocytes in mice model of diabetic nephropathy [25].…”