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Activation of integrin-linked kinase (ILK) and Wnt signaling pathway after podocyte damage in proteinuric disease: a possible pathogenetic mechanism


As a component of the glomerular filtration barrier, the podocyte is a target of injury in many glomerular diseases and podocyte cell shape changes, including foot process effacement and detachment from glomerular basement membrane (GBM), occur in virtually all proteinuric diseases. It lies outside the glomerular capillary connected via progressive cytoplasmic branches to the foot processes that are anchored to the GBM. Foot processes are elongated cytoplasmic processes that interdigitate with foot processes from adjacent podocytes to completely cover the external surface of the glomerular capillaries. The anchorage to the GMB is mediated by an a3b1-integrin complex present in the focal contacts at the sole of the foot processes which are linked to a contractile structure containing actin, myosin, a-actinin, talin and vinculin. Blockade of glomerular integrins with antibodies or RGD peptides results in proteinuria. Furthermore, a3-integrin knockout mouse present nephrotic syndrome.Integrins can activate a wide range of intracellular signaling pathways, even though they lack intrinsic enzymatic activity. Their cytoplasmic tails bind to signaling molecules, such as kinases, which then initiate signaling cascades after integrin ligation. Biochemical studies have identified several cytoskeletal and potential regulatory molecules that can interact directly with integrin beta subunits. For the beta1 integrins, direct binding was reported in vitro for talin, a-actinin, tensin, focal adhesion kinase (FAK) and integrin-linked kinase. The integrin-linked kinase (ILK) is a newly identified ankyrin-repeat containing serine/threonine protein kinase. It presents a relatively strong association with the integrin b1 and b3 subunit cytoplasmic domains, and is involved in bidirectional signal transduction, through integrin binding to matrix molecules. ILK has been implicated in cellular control of integrin-mediated cell-matrix interactions and cell proliferation. Its overexpression in epithelial cells resulted in a disorganization of cell-cell adhesion, probably caused by inhibition in the expression of E-cadherin. Furthermore, those ILK overexpressing epithelial cells acquire mesenchymal characteristics. Phenotipical transformation is found during normal embryonic development and in some pathologic processes. During embriogenesis, that morphogenetic effect is accomplished by activation of the Wnt signaling pathway, a vertebrate homolog of Drosophila Wingless. Wnt proteins are components of a large family of cysteine-rich secreted molecules associated with the extracellular matrix. They control embryonic patterning and cell-fate decisions in development. A central feature of this signaling pathway is the stabilization of a cytosolic pool of beta-catenin, translocation of beta-catenin to the nucleus where it interacts with members of the lymphoid enhancer factor I (LEF)/T-cell factor (TCF) family of transcription factors. The activation of this transcriptional complex leads to the stimulation of expression and/or repression of several genes, inclusive mesenchymal genes. ILK overexpression in two independent epithelial cells systems resulted in nuclear localization of beta-catenin and increased transcriptional activation by LEF-1, indicating its implication with the Wnt pathwayWe have recently reported on the involvement of ILK in the pathogenesis of some proteinuric kidney diseases. In another study with an in vitro model of podocyte lesion, we could also show nuclear translocation of beta-catenin and de novo expression of LEF-1. In this study we intend to show that activated ILK can trigger the wnt signaling pathway in podocytes. This activation could be responsible for phenotype changes and contribute to those events leading to the failure of filtration barrier. This is a new field of research that can uncover pathophysiologic pathways and potential targets for therapeutic intervention in podocyte diseases. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
NAVES, MARCELO A.; REQUIAO-MOURA, LUCIO R.; SOARES, MARIA F.; SILVA-JUNIOR, JOSE A.; MASTROIANNI-KIRSZTAJN, GIANNA; TEIXEIRA, VICENTE P. C.. Podocyte Wnt/beta-catenin pathway is activated by integrin-linked kinase in clinical and experimental focal segmental glomerulosclerosis. JOURNAL OF NEPHROLOGY, v. 25, n. 3, p. 401-409, . (05/01202-0)

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