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Nuclear receptors in podocyte biology and glomerular disease

Abstract

Nuclear receptors have a broad spectrum of biological functions in normal physiology and in the pathology of various diseases, including glomerular disease. The primary therapies for many glomerular diseases are glucocorticoids, which exert their immunosuppressive and direct podocyte protective effects via the glucocorticoid receptor (GR). As glucocorticoids are associated with important adverse effects and a substantial proportion of patients show resistance to these therapies, the beneficial effects of selective GR modulators are now being explored. Peroxisome proliferator-activated receptor-γ (PPARγ) agonism using thiazolidinediones has potent podocyte cytoprotective and nephroprotective effects. Repurposing of thiazolidinediones or identification of novel PPARγ modulators are potential strategies to treat non-diabetic glomerular disease. Retinoic acid receptor-α is the key mediator of the renal protective effects of retinoic acid, and repair of the endogenous retinoic acid pathway offers another potential therapeutic strategy for glomerular disease. Vitamin D receptor, oestrogen receptor and mineralocorticoid receptor modulators regulate podocyte injury in experimental models. Further studies are needed to better understand the mechanisms of these nuclear receptors, evaluate their synergistic pathways and identify their novel modulators. Here, we focus on the role of nuclear receptors in podocyte biology and non-diabetic glomerular disease.

Key points

  • Understanding the role of nuclear receptors in podocyte biology and glomerular disease could lead to novel therapeutic strategies for glomerular disease.

  • Glucocorticoids activate the glucocorticoid receptor and have direct protective effects on podocytes in addition to their immunosuppressive effects; glucocorticoid resistance and adverse effects pose huge challenges to the therapeutic use of these agents.

  • Activation of peroxisome proliferator-activated receptor-γ using thiazolidinediones protects against podocyte injury and has beneficial effects in animal models of glomerular disease.

  • Retinoic acid receptor-α mediates the renal protective effects of retinoic acid; repair of the endogenous retinoic acid synthesis pathway might be a novel strategy to treat glomerular disease.

  • Vitamin D3 activates the vitamin D receptor and ameliorates podocyte injury in experimental models; the available data from clinical trials of vitamin D supplementation in patients with chronic kidney disease are inconclusive.

  • A deeper understanding of the mechanisms, synergistic pathways and modulated targeting of nuclear receptor pathways in podocyte biology could enable the development of more effective therapies for non-diabetic glomerular disease.

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Fig. 1: GR signalling in podocytes.
Fig. 2: PPARγ signalling in adipocytes and in podocytes.
Fig. 3: RAR signalling in podocytes and glomerular disease.
Fig. 4: VDR signalling in podocytes.
Fig. 5: MR signalling in podocytes.
Fig. 6: ER signalling in podocytes.
Fig. 7: Crosstalk between nuclear receptors signalling pathways in podocytes.

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Acknowledgements

The authors’ work is supported by funding from the American Heart Association Career Development Award (18CDA34110287) and by the Nationwide Children’s Hospital to S.A.; VA Merit Award IBX000345C, NIH 1R01DK088541 and NIH P01DK56492 to J.C.H.; and by Institut National de Santé et de la Recherche Médicale (INSERM) and research grants from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ ERC grant agreement no. 107037) and SWITCHES grant (ANR12-BSV1-0039-03) from l’Agence Nationale de la Recherche (ANR) of France to P.-L.T.

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All authors contributed to researching data, and writing, reviewing and editing the article. S.A. focused on GR, PPARγ, ER and VDR, and drafted the figures. P.-L.T. focused on PPARγ and MR, and J.C.H. focused on RAR and RXR.

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Correspondence to Shipra Agrawal.

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Nature Reviews Nephrology thanks P. Brinkkoetter, C. Faul and M. Moeller for their contribution to the peer review of this work.

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Glossary

Co-regulators

Co-activators or co-repressors that bind to a nuclear receptor in the absence or presence of ligands enabling activation or repression of gene transcription.

Sumoylation

A reversible post-translational protein modification that consists of the covalent labelling of a small protein called SUMO to lysine residues of selected target proteins. Sumoylation is a well-characterized regulator of nuclear functions.

Transactivation

The most common mechanism of nuclear receptor action that involves direct binding of the nuclear receptor to a DNA hormone response element.

Transrepression

The process by which nuclear receptors bind to and deactivate other transcription factors; for example, the glucocorticoid receptor and PPARγ can suppress target genes by inhibiting the activities of other transcription factors, such as AP-1, in a ligand-dependent manner; transrepression does not require the nuclear receptor to bind DNA.

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Agrawal, S., He, J.C. & Tharaux, PL. Nuclear receptors in podocyte biology and glomerular disease. Nat Rev Nephrol 17, 185–204 (2021). https://doi.org/10.1038/s41581-020-00339-6

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