Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5507735 | Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | 2017 | 14 Pages |
Abstract
Two processes are associated with progressive loss of renal function: 1) decreased aquaporin-2 (AQP2) expression and urinary concentrating capacity (Nephrogenic Diabetes Insipidus, NDI); and 2) changes in extracellular matrix (ECM) composition, e.g. increased collagen I (Col I) deposition, characteristic of tubule-interstitial fibrosis. AQP2 expression is regulated by both the ECM-to-intracellular scaffold protein integrin-linked kinase (ILK) by NFATc/AP1 and other transcription factors. In the present work, we used in vivo and in vitro approaches to examine ILK participation in NFATc3/AP-1-mediated increases in AQP2 gene expression. Both NFATc3 knock-out mice and ILK conditional-knockdown mice (cKD-ILK) display symptoms of NDI (polyuria and reduced AQP2 expression). NFATc3 is upregulated in the renal medulla tubular cells of cKD-ILK mice but with reduced nuclear localization. Inner medullary collecting duct mIMCD3 cells were subjected to ILK depletion and transfected with reporter plasmids. Pharmacological activators or inhibitors determined the effect of ILK activity on NFATc/AP-1-dependent increases in transcription of AQP2. Finally, mIMCD3 cultured on Col I showed reduced activity of the ILK/GSK3β/NFATc/AQP2 axis, suggesting this pathway is a potential target for therapeutic treatment of NDI.
Keywords
ionomycini.p.b.w.AP-14-hydroxytamoxifenp-GSK3βGSK3βp-CREBphorbol 12-myristate 13-acetateAQP2ECMCrm1Aquaporin-2NFATc3V2RV2 vasopressin receptorDMEM-F12CosmRhoA/Rho kinaseAquaporin 2NFATCREPBSCH2OCREBNDINF-κBPMAILKLOXCSAIntraperitoneallyNephrogenic diabetes insipidusembryonic stemCyclosporine Anuclear factor of activated T-cellsnuclear factor kappa-light-chain-enhancer of activated B cellsLeptomycin BExtracellular matrixPhosphate-buffered salinewild-typebody weightVehicleactivator protein-1cAMP response element-binding proteinintegrin linked kinaseGelGelatinCol ICalcineurinControlintegrin-linked kinaseglycogen synthase kinase-3betaRock
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Biochemistry
Authors
Marco Hatem-Vaquero, Mercedes Griera, Wieslawa Giermakowska, Alicia Luengo, Laura Calleros, Laura V. Gonzalez Bosc, Diego RodrÃguez-Puyol, Manuel RodrÃguez-Puyol, Sergio De Frutos,