Inhibition of the glucocorticoid receptor attenuates proteinuric kidney diseases in multiple species
Year: 2023
Type: article
Abstract: BACKGROUND: Glucocorticoids are the treatment of choice for proteinuric patients with minimal change disease (MCD) and primary focal 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.
DOI: 10.1093/ndt/gfad254
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,442
Funders: American Heart Association, Nationwide Children's Hospital, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, RWTH Aachen University, European Rare Kidney Disease Reference Network, Stony Brook University, European Research Council, National Institute of Diabetes and Digestive and Kidney Diseases, H2020 European Research Council
Awards: Translationale Nephropathologie, G1860250122, Die Rolle von epithelialen CD74 in Nierenerkrankungen, STOP-FSGS - Translationaler Forschungsverbund zur Verbesserung der Diagnostik und Therapie der FSGS, TP 1: Rolle des MIF-Signalwegs bei FSGS, TP 4: Pathogenese und neue therapeutische Ansätze, G3703647185, G410390351, STOP-FSGS - Translationaler Forschungsverbund zur Verbesserung der Diagnostik und Therapie der FSGS, Histopathologische Bildanalyse und Analyse von pathogenen Signalwegen, KFO 5011: Integration neuer Methoden zur Verbesserung von translationaler Nierenforschung, AI-augmented, Multiscale Image-based Diagnostics of Chronic Kidney Disease, G7683938089, TRR 219: Mechanismen kardiovaskulärer Komplikationen bei chronischer Niereninsuffizienz, Mechanisms and Selective Modulation of PPARy for the Treatment of Podocytopathies, G916432086
OpenAlex ID: W4389217919