Investigations of Glucocorticoid Action in GN.

Christoph Kuppe, Claudia van Roeyen, Katja Leuchtle, Nazanin Kabgani, Michael Vogt, Marc Van Zandvoort, Bart Smeets, Jürgen Floege, Hermann-Josef Gröne, Marcus J Moeller

Journal of the American Society of Nephrology : JASN 2017 May

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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/fl mice. Pax8-Cre/GRfl/fl mice 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. Copyright © 2017 by the American Society of Nephrology.

Citation

Christoph Kuppe, Claudia van Roeyen, Katja Leuchtle, Nazanin Kabgani, Michael Vogt, Marc Van Zandvoort, Bart Smeets, Jürgen Floege, Hermann-Josef Gröne, Marcus J Moeller. Investigations of Glucocorticoid Action in GN. Journal of the American Society of Nephrology : JASN. 2017 May;28(5):1408-1420