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

肾小球足细胞在肾小球疾病的发生发展过程中起着中心作用。它们表现出复杂的形态和细胞过程。足细胞间的连接--裂隙-横隔膜--位于这些细胞突起之间。缝隙横隔膜是正常使用的肾脏过滤器所必需的。神经元也表现出分化的细胞过程。有组织的神经元过程通过混合分泌的指导线索来发展，这些线索通过与特定的神经元受体结合来协调过程的形成。其中许多引导信号在足细胞中表达，并在足细胞过程的发育和损伤重塑中发挥作用。神经营养受体酪氨酸激酶3(NTRK3)是一种神经导向受体，表达于足细胞。我们发现，NTRK3通过ERK介导的WAVE2激活向肌动蛋白细胞骨架发出信号，启动足细胞迁移。肾单位特异性NTRK3基因敲除小鼠在足细胞早期被敲除，其表型使人联想到正常血糖环境下的糖尿病肾病。我们对与NTRK3配体孵育的高表达NTRK3的足细胞进行的磷酸化蛋白质组分析表明，在胰岛素相关、Erb-B2受体酪氨酸激酶(ErbB)相关的信号以及代谢和线粒体过程中，磷酸肽过表达。此外，我们还发现，NTRK3配体刺激培养的足细胞可导致胰岛素生长因子1受体(IGF1R)的反式激活。我们的假设是，NTRK3通过调节代谢信号(IGF1R或ErbB相关)和线粒体过程参与糖尿病肾病的发生发展。我们现在将在培养的足细胞和我们的基因敲除小鼠中剖析NTRK3与IGF1R和ErbB受体的信号串扰。我们将分析NTRK3如何调节培养的足细胞和NTRK3基因敲除小鼠模型中的线粒体过程。此外，我们将通过对肾脏和足细胞特异性NTRK3过度表达的糖尿病肾病进行化学模型研究NTRK3在糖尿病肾病中的作用。

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.