title: Paricalcitol Inhibits Aldosterone-Induced Proinflammatory Factors by Modulating Epidermal Growth Factor Receptor Pathway in Cultured Tubular Epithelial Cells.
abstract: Chronic kidney disease is characterized by Vitamin D deficiency and activation of the renin-angiotensin-aldosterone system. Increasing data show that vitamin D receptor agonists (VDRAs) exert beneficial effects in renal disease and possess anti-inflammatory properties, but the underlying mechanism remains unknown. Emerging evidence suggests that "a disintegrin and metalloproteinase" (ADAM)/epidermal growth factor receptor (EGFR) signalling axis contributes to renal damage. Aldosterone induces EGFR transactivation regulating several processes including cell proliferation and fibrosis. However, data on tubular epithelial cells is scarce. We have found that, in cultured tubular epithelial cells, aldosterone induced EGFR transactivation via TGF-α/ADAM17. Blockade of the TGF-α/ADAM17/EGFR pathway inhibited aldosterone-induced proinflammatory gene upregulation. Moreover, among the potential downstream mechanisms, we found that TGF-α/ADAM17/EGFR inhibition blocked ERK and STAT-1 activation in response to aldosterone. Next, we investigated the involvement of TGF-α/ADAM17/EGFR axis in VDRA anti-inflammatory effects. Preincubation with the VDRA paricalcitol inhibited aldosterone-induced EGFR transactivation, TGF-α/ADAM-17 gene upregulation, and downstream mechanisms, including proinflammatory factors overexpression. In conclusion, our data suggest that the anti-inflammatory actions of paricalcitol in tubular cells could depend on the inhibition of TGF-α/ADAM17/EGFR pathway in response to aldosterone, showing an important mechanism of VDRAs action.
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jimenez Diaz, Universidad Autónoma Madrid (UAM), 28040 Madrid, Spain ; REDINREN, Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Morgado-Pascual
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jimenez Diaz, Universidad Autónoma Madrid (UAM), 28040 Madrid, Spain ; REDINREN, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rayego-Mateos
authors.affiliation: REDINREN, Madrid, Spain ; Department of Experimental Nephrology, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, 25198 Lleida, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Valdivielso
authors.affiliation: REDINREN, Madrid, Spain ; Dialysis Unit, IIS-Fundación Jiménez Díaz, School of Medicine, UAM, Madrid, Spain ; Institute of Renal Research Queen Sophia (IRSIN), Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Institute of Renal Research Queen Sophia (IRSIN), Spain ; Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain ; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jimenez Diaz, Universidad Autónoma Madrid (UAM), 28040 Madrid, Spain ; REDINREN, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072198:ADAM17 Protein; D000450:Aldosterone / Q000008:administration & dosage / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D004872:Ergocalciferols / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D018167:Receptors, Calcitriol / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis* / Q000235:genetics; D014808:Vitamin D Deficiency / Q000235:genetics / Q000473:pathology
chemical_list: D004872:Ergocalciferols; D018167:Receptors, Calcitriol; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D016211:Transforming Growth Factor alpha; D000450:Aldosterone; C084656:paricalcitol; C512478:EGFR protein, human; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human