The role of Neurotrophic receptor kinase 3 (Ntrk3) in podocyte disease.

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Kidney podocytes are central during development of glomerular disease. They exhibit a complex morphology with cellular processes. The podocyte intercellular junction – the slit-diaphragm – is localized between these cellular processes. The slit-diaphragm is essential for a functional kidney filter. Neurons also show differentiated cellular processes. Organized neuronal processes develop by a blend of secreted guidance cues which orchestrate process formation by binding to specific neuronal receptors. Many of these guidance cues are expressed in podocytes and instrumental in podocyte process development and injury remodeling. Neurotrophic Receptor Tyrosine Kinase 3 (Ntrk3) is a neuronal guidance receptor which is expressed in podocytes. We showed that Ntrk3 signals to the Actin cytoskeleton by Erk-mediated WAVE2 activation to initiate podocyte migration. Nephron-specific Ntrk3 knockout mice with early knockout in podocytes show a phenotype reminiscent of diabetic nephropathy in a normoglycemic environment. We showed in a phospho-proteome analysis of podocytes overexpressing Ntrk3 that were incubated with the Ntrk3 ligand that phospho-peptides were overrepresented in Insulin-associated, Erb-B2 Receptor Tyrosine Kinase (ErbB)-associated signaling and metabolic and mitochondrial processes. Additionally, we showed that stimulation of cultured podocytes with the Ntrk3 ligand resulted in trans-activation of the Insulin growth factor 1 Receptor (Igf1R). Our hypothesis is that Ntrk3 is involved in the development of diabetic nephropathy mediated by regulating metabolic signaling (Igf1R or ErbB-associated) and mitochondrial processes. We will now dissect signal cross-talk of Ntrk3 with Igf1R and ErbB receptors in cultivated podocytes and in our knockout mice. We will analyze how Ntrk3 regulates mitochondrial processes in cultured podocytes and the Ntrk3 knockout mouse model. Furthermore, we will study the role of Ntrk3 in developing diabetic nephropathy by performing a chemical model of diabetic nephropathy on nephron- and podocyte-specific Ntrk3 overexpressing background.