Inhibition of the glucocorticoid receptor attenuates proteinuric kidney diseases in multiple species

Eleni Stamellou; Shipra Agrawal; Florian Siegerist; Marc Buse; Christoph Kuppe; Tim Lange; Eva Miriam Buhl; Jessica Alam; Thiago Strieder; Peter Boor; Tammo Ostendorf; Hermann-Josef Gröne; Jürgen Floege; William E Smoyer; Nicole Endlich; Marcus J Moeller

doi:10.1093/ndt/gfad254

Inhibition of the glucocorticoid receptor attenuates proteinuric kidney diseases in multiple species

Nephrol Dial Transplant. 2023 Nov 30:gfad254. doi: 10.1093/ndt/gfad254. Online ahead of print.

Authors

Eleni Stamellou^{1

2

3}, Shipra Agrawal⁴, Florian Siegerist⁵, Marc Buse¹, Christoph Kuppe^{1

6}, Tim Lange⁵, Eva Miriam Buhl², Jessica Alam¹, Thiago Strieder¹, Peter Boor^{1

2}, Tammo Ostendorf¹, Hermann-Josef Gröne⁷, Jürgen Floege¹, William E Smoyer⁸, Nicole Endlich^{5

9}, Marcus J Moeller¹

Affiliations

¹ Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
² Institute of Pathology and Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany.
³ Department of Nephrology, Medical School, University of Ioannina, Ioannina, Greece.
⁴ Division of Nephrology and Hypertension, Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
⁵ Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany.
⁶ Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany.
⁷ Institute of Pharmacology, Philipps- University of Marburg, Germany.
⁸ Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, College of Medicine, Columbus, OH,USA.
⁹ NIPOKA, Greifswald, Germany.

PMID: 38037533
DOI: 10.1093/ndt/gfad254

Abstract

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.

Keywords: FSGS; MCD; glucocorticoid receptor (GR); mifepristone; podocyte; proteinuria.