PUBLICATION
Inhibition of the glucocorticoid receptor attenuates proteinuric kidney diseases in multiple species
- Authors
- Stamellou, E., Agrawal, S., Siegerist, F., Buse, M., Kuppe, C., Lange, T., Buhl, E.M., Alam, J., Strieder, T., Boor, P., Ostendorf, T., Gröne, H.J., Floege, J., Smoyer, W.E., Endlich, N., Moeller, M.J.
- ID
- ZDB-PUB-231201-13
- Date
- 2023
- Source
- Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 39(7): 1181-1193 (Journal)
- Registered Authors
- Keywords
- FSGS, MCD, glucocorticoid receptor (GR), mifepristone, podocyte, proteinuria
- MeSH Terms
-
- Animals
- Disease Models, Animal
- Female
- Glomerulosclerosis, Focal Segmental/drug therapy
- Glomerulosclerosis, Focal Segmental/metabolism
- Glomerulosclerosis, Focal Segmental/pathology
- Hormone Antagonists/pharmacology
- Humans
- Kidney Diseases/drug therapy
- Kidney Diseases/etiology
- Kidney Diseases/metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Mifepristone/pharmacology
- Nephrosis, Lipoid/drug therapy
- Nephrosis, Lipoid/metabolism
- Podocytes*/drug effects
- Podocytes*/metabolism
- Podocytes*/pathology
- Proteinuria*/drug therapy
- Proteinuria*/etiology
- Proteinuria*/metabolism
- Puromycin Aminonucleoside
- Rats
- Receptors, Glucocorticoid*/antagonists & inhibitors
- Receptors, Glucocorticoid*/metabolism
- Zebrafish*
- PubMed
- 38037533 Full text @ Nephrol. Dial. Transplant.
Citation
Stamellou, E., Agrawal, S., Siegerist, F., Buse, M., Kuppe, C., Lange, T., Buhl, E.M., Alam, J., Strieder, T., Boor, P., Ostendorf, T., Gröne, H.J., Floege, J., Smoyer, W.E., Endlich, N., Moeller, M.J. (2023) Inhibition of the glucocorticoid receptor attenuates proteinuric kidney diseases in multiple species. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 39(7):1181-1193.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping