2024-03-29T09:49:00Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1250072021-07-20T11:30:12Zcom_10261_22com_10261_1col_10261_275
IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes
Santamaria, Beatriz
González-Rodríguez, Águeda
Ortiz, Alberto
Valverde, Ángela M.
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España)
Comunidad de Madrid
Ministerio de Economía y Competitividad (España)
Instituto de Salud Carlos III
Medical Research Council (UK)
Kidney Research UK
Diabetes UK
Biotechnology and Biological Sciences Research Council (UK)
Northern Ireland Kidney Research Fund
Department for Employment and Learning (Northern Ireland)
Irish Government
et al.
Insulin signaling to the glomerular podocyte is important for normal kidney function and is implicated in the pathogenesis of diabetic nephropathy (DN). This study determined the role of the insulin receptor substrate 2 (IRS2) in this system. Conditionally immortalized murine podocytes were generated from wild-type (WT) and insulin receptor substrate 2-deficient mice (Irs2-/-). Insulin signaling, glucose transport, cellular motility and cytoskeleton rearrangement were then analyzed. Within the glomerulus IRS2 is enriched in the podocyte and is preferentially phosphorylated by insulin in comparison to IRS1. Irs2-/- podocytes are significantly insulin resistant in respect to AKT signaling, insulin-stimulated GLUT4-mediated glucose uptake, filamentous actin (F-actin) cytoskeleton remodeling and cell motility. Mechanistically, we discovered that Irs2 deficiency causes insulin resistance through up-regulation of the phosphatase and tensin homolog (PTEN). Importantly, suppressing PTEN in Irs2-/- podocytes rescued insulin sensitivity. In conclusion, this study has identified for the first time IRS2 as a critical molecule for sensitizing the podocyte to insulin actions through its ability to modulate PTEN expression. This finding reveals two potential molecular targets in the podocyte for modulating insulin sensitivity and treating DN.
2015-11-13T11:46:29Z
2015-11-13T11:46:29Z
2015
2015-11-13T11:46:30Z
artículo
BBA - Molecular Cell Research 1853(12): 3224-3234 (2015)
http://hdl.handle.net/10261/125007
10.1016/j.bbamcr.2015.09.020
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100000265
http://dx.doi.org/10.13039/501100000291
http://dx.doi.org/10.13039/501100000361
http://dx.doi.org/10.13039/501100000268
http://dx.doi.org/10.13039/100008303
http://dx.doi.org/10.13039/100012818
eng
Sí
S2010/BMD-2423/MOIR
closedAccess
Elsevier