Your browser doesn't support javascript.
loading
Inhibition of the glucocorticoid receptor attenuates proteinuric kidney diseases in multiple species.
Stamellou, Eleni; Agrawal, Shipra; Siegerist, Florian; Buse, Marc; Kuppe, Christoph; Lange, Tim; Buhl, Eva Miriam; Alam, Jessica; Strieder, Thiago; Boor, Peter; Ostendorf, Tammo; Gröne, Hermann-Josef; Floege, Jürgen; Smoyer, William E; Endlich, Nicole; Moeller, Marcus J.
Afiliação
  • Stamellou E; Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
  • Agrawal S; Institute of Pathology and Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany.
  • Siegerist F; Department of Nephrology, Medical School, University of Ioannina, Ioannina, Greece.
  • Buse M; Division of Nephrology and Hypertension, Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • Kuppe C; Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
  • Lange T; Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
  • Buhl EM; Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
  • Alam J; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.
  • Strieder T; Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
  • Boor P; Institute of Pathology and Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany.
  • Ostendorf T; Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
  • Gröne HJ; Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
  • Floege J; Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
  • Smoyer WE; Institute of Pathology and Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany.
  • Endlich N; Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
  • Moeller MJ; Institute of Pharmacology, Philipps- University of Marburg, Germany.
Article em En | MEDLINE | ID: mdl-38037533
BACKGROUND AND HYPOTHESIS: Glucocorticoids are the treatment of choice for proteinuric patients with minimal-change disease (MCD) and primary focal and segmental glomerulosclerosis (FSGS). Immunosuppressive as well as direct effects on podocytes are believed to mediate their actions. In this study, we analyzed the anti-proteinuric effects of inhibition of the glucocorticoid receptor (GR) in glomerular epithelial cells, including podocytes. METHODS: We employed genetic and pharmacological approaches to inhibit the GR. Genetically, we used Pax8-Cre/GRfl/fl mice to specifically inactivate the GR in kidney epithelial cells. Pharmacologically, we utilized a glucocorticoid antagonist called mifepristone. RESULTS: Genetic inactivation of GR, specifically in kidney epithelial cells, using Pax8-Cre/GRfl/fl mice, ameliorated proteinuria following protein overload. We further tested the effects of pharmacological GR inhibition in three models and species: the puromycin-aminonucleoside-induced nephrosis model in rats, the protein overload model in mice and the inducible transgenic NTR/MTZ zebrafish larvae with specific and reversible podocyte injury. In all three models, both pharmacological GR activation and inhibition consistently and significantly ameliorated proteinuria. Additionally, we translated our findings to humans, where three nephrotic adult patients with MCD or primary FSGS with contraindications or insufficient responses to corticosteroids, were treated with mifepristone. This treatment resulted in a clinically relevant reduction of proteinuria. CONCLUSIONS: Thus, across multiple species and proteinuria models, both genetic and pharmacological GR inhibition was at least as effective as pronounced GR activation. While, the mechanism remains perplexing, GR inhibition may be a novel and targeted therapeutic approach to treat glomerular proteinuria potentially bypassing adverse actions of steroids.
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article