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.