title: Investigations of Glucocorticoid Action in GN.
abstract: For several decades, glucocorticoids have been used empirically to treat rapid progressive GN. It is commonly assumed that glucocorticoids act primarily by dampening the immune response, but the mechanisms remain incompletely understood. In this study, we inactivated the glucocorticoid receptor (GR) specifically in kidney epithelial cells using Pax8-Cre/GRfl/flmice. Pax8-Cre/GRfl/flmice did not exhibit an overt spontaneous phenotype. In mice treated with nephrotoxic serum to induce crescentic nephritis (rapidly progressive GN), this genetic inactivation of the GR in kidney epithelial cells exerted renal benefits, including inhibition of albuminuria and cellular crescent formation, similar to the renal benefits observed with high-dose prednisolone in control mice. However, genetic inactivation of the GR in kidney epithelial cells did not induce the immunosuppressive effects observed with prednisolone.In vitro, prednisolone and the pharmacologic GR antagonist mifepristone each acted directly on primary cultures of parietal epithelial cells, inhibiting cellular outgrowth and proliferation. In wild-type mice, pharmacologic treatment with the GR antagonist mifepristone also attenuated disease as effectively as high-dose prednisolone without the systemic immunosuppressive effects. Collectively, these data show that glucocorticoids act directly on activated glomerular parietal epithelial cells in crescentic nephritis. Furthermore, we identified a novel therapeutic approach in crescentic nephritis, that of glucocorticoid antagonism, which was at least as effective as high-dose prednisolone with potentially fewer adverse effects.
authors.affiliation: Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kuppe
authors.affiliation: Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: van Roeyen
authors.affiliation: Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.|Interdisciplinary Centre for Clinical Research, Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, Aachen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Leuchtle
authors.affiliation: Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
authors.forename: Nazanin
authors.initials: N
authors.lastname: Kabgani
authors.affiliation: Interdisciplinary Centre for Clinical Research, Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, Aachen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Vogt
authors.affiliation: Interdisciplinary Centre for Clinical Research, Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, Aachen, Germany.|Department of Genetics and Cell Biology, Sector Molecular Cell Biology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Van Zandvoort
authors.affiliation: Department of Pathology, Radboud University, Nijmegen, The Netherlands; and.
authors.forename: Bart
authors.initials: B
authors.lastname: Smeets
authors.affiliation: Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.affiliation: Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany; mmoeller@ukaachen.de.|Interdisciplinary Centre for Clinical Research, Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, Aachen, Germany.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Moeller
mesh_terms: D000818:Animals; D004848:Epithelium; D005921:Glomerulonephritis / Q000188:drug therapy*; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D011239:Prednisolone; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D011239:Prednisolone
keywords: cortisol; glomerulonephritis; parietal epithelial cells; podocyte