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

2020 ◽  
pp. ASN.2020040424
Author(s):  
Carolin Lepa ◽  
Sascha Hoppe ◽  
Antje Stöber ◽  
Boris V. Skryabin ◽  
Laura Katharina Sievers ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Glomerular Disease ◽  
Tyrosine Kinase Receptor ◽  
Glomerular Diseases ◽  
Basement Membrane Thickening ◽  
Neurotrophin 3 ◽  
Podocyte Loss ◽  
Nephron Development ◽  
Igf1r Signaling ◽  
Igf1 Receptor

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.

scholarly journals Inactivation of mediator complex protein 22 in podocytes results in intracellular vacuole formation, podocyte loss and premature death

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Patricia Q. Rodriguez ◽  
David Unnersjö-Jess ◽  
Sonia S. Zambrano ◽  
Jing Guo ◽  
Katja Möller-Hackbarth ◽  
...  
Keyword(s):  
Critical Role ◽  
Kidney Tissue ◽  
Premature Death ◽  
Glomerular Disease ◽  
Mediator Complex ◽  
Glomerular Diseases ◽  
Vacuole Formation ◽  
Podocyte Loss ◽  
Complex Protein ◽  
Intracellular Vacuole

AbstractPodocytes are critical for the maintenance of kidney ultrafiltration barrier and play a key role in the progression of glomerular diseases. Although mediator complex proteins have been shown to be important for many physiological and pathological processes, their role in kidney tissue has not been studied. In this study, we identified a mediator complex protein 22 (Med22) as a renal podocyte cell-enriched molecule. Podocyte-specific Med22 knockout mouse showed that Med22 was not needed for normal podocyte maturation. However, it was critical for the maintenance of podocyte health as the mice developed progressive glomerular disease and died due to renal failure. Detailed morphological analyses showed that Med22-deficiency in podocytes resulted in intracellular vacuole formation followed by podocyte loss. Moreover, Med22-deficiency in younger mice promoted the progression of glomerular disease, suggesting Med22-mediated processes may have a role in the development of glomerulopathies. This study shows for the first time that mediator complex has a critical role in kidney physiology.

scholarly journals Neurotrophin-3 and FLT3 Tyrosine Kinase Receptor in Perinatal Life

2005 ◽  
Vol 2005 (1) ◽  
pp. 53-56 ◽  
Author(s):  
Ariadne Malamitsi-Puchner ◽  
Emmanouel Economou ◽  
Theodora Boutsikou ◽  
Konstantinos E. Nikolaou ◽  
Nikolaos Vrachnis
Keyword(s):  
Immune Response ◽  
Tyrosine Kinase ◽  
Nervous Tissue ◽  
Tyrosine Kinase Receptor ◽  
Term Infants ◽  
Postnatal Brain ◽  
Neonatal Life ◽  
Neurotrophin 3 ◽  
Low Levels ◽  
Circulating Levels

Our aim is to determine—in 30 healthy full-term infants and their mothers—circulating levels of neurotrophin-3 (NT-3) (important for antenatal and postnatal brain development and implicated in the immune response) and FLT3 tyrosine kinase receptor (FLT3) (controlling hematopoiesis and found in the nervous tissue), in the fetal and neonatal life. NT-3 levels, in contrast to FLT3 ones, increased significantly on the fourth postnatal day in relation to the low levels found in the mother, fetus, and day 1 neonate (P=.03, respectively). Maternal and umbilical NT3 levels positively correlated with respective FLT3 levels (P=.003andP=.03). Circulating NT-3 levels increased in early neonatal life, possibly due to exposure to various stimuli soon after birth. FLT3 levels do not seem to behave accordingly, although these two substances probably synergize.

The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor

Cell ◽  
1991 ◽  
Vol 65 (5) ◽  
pp. 895-903 ◽  
Author(s):  
Dan Soppet ◽  
Enrique Escandon ◽  
Johnne Maragos ◽  
David S. Middlemas ◽  
Susan W. Raid ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Neurotrophic Factors ◽  
Neurotrophic Factor ◽  
Brain Derived Neurotrophic Factor ◽  
Tyrosine Kinase Receptor ◽  
Neurotrophin 3

scholarly journals Podocytes and Proteinuric Kidney Disease

2015 ◽  
Vol 12 (1) ◽  
pp. 16-19
Author(s):  
Alketa Koroshi ◽  
Alma Idrizi
Keyword(s):  
Treatment Strategies ◽  
Glomerular Disease ◽  
Glomerular Sclerosis ◽  
Endstage Renal Disease ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Glomerular Function ◽  
Podocyte Loss ◽  
Insight Into

Abstract Glomerular disease is the most common cause of endstage renal disease (ESRD), accounting for almost two thirds of cases. In glomerular disease, alterations of po-docytes are of particular importance. Podocyte loss represents a central mediator of glomerular sclerosis. Toxic, genetic, immune, infectious, oxidant, metabolic, hemody-namic, and other mechanisms can all target the podo-cytes. These mechanisms provide new insight into the unique dynamic microenvironment that each individual podocyte inhabits and how it can turn hostile to survival. At the same time, they raise new therapeutic challenges to preserve glomerular function by containing podocyte injury and limiting its spread, both in podo-cytopathies and in other progressive glomerular diseases. Treatment strategies should aim at enhancing podocyte survival. The renin-angiotensin axis blockade, apart from its antifibrotic and intraglomerular hemodynamic effects, has an important role in preventing podocyte loss. However, only long-term observational studies can clarify if many patients will benefit from podocyte-targeted treatment such as abatacept or similar agents.

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