Glucocorticoids in the Treatment of Glomerular Diseases: Pitfalls and Pearls

Abstract

Glucocorticoids exert anti-inflammatory and immunosuppressive activities by genomic and nongenomic effects. The classic genomic effects are mediated by cytosolic glucocorticoid receptors that can upregulate the expression of anti-inflammatory proteins in the nucleus (transactivation) or repress the translocation of proinflammatory transcription factors from the cytosol into the nucleus (transrepression). The nongenomic effects are probably mediated by membrane glucocorticoid receptors. Glucocorticoid receptors are expressed also in podocytes and experimental data suggest that glucocorticoids may protect from podocyte injury. Glucocorticoids have a low therapeutic index and may exert a number of time-dependent and dose-dependent side effects. Measures to prevent or attenuate side effects include single-morning administration of short-acting glucocorticoids, dietetic counseling, increasing physical activity, frequent monitoring, and adapting the doses to the clinical conditions of the patient. Synthetic glucocorticoids, either given alone or in combination with other immunosuppressive drugs, are still the cornerstone therapy in multiple glomerular disorders. However, glucocorticoids are of little benefit in C3 glomerulopathy and may be potentially deleterious in patients with maladaptive focal glomerulosclerosis. Their efficacy depends not only on the type and severity of glomerular disease, but also on the timeliness of administration, the dosage, and the duration of treatment. Whereas an excessive use of glucocorticoids can be responsible for severe toxicity, too low a dosage and too short duration of glucocorticoid treatment can result in false steroid resistance.

Keywords: Anti-Inflammatory Agents; Counseling; Cytosol; Dietetics; Exercise; Genomics; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunosuppressive Agents; Kidney Glomerulus; Podocytes; Receptors, Glucocorticoid; Steroids; Therapeutic Index; Transcriptional Activation; cortisol; immunosuppression; primary glomerulonephritis; transcription factors.

Figure 1.

The anti-inflammatory and immunosuppressive activity of glucocorticoids is mediated primarily by genomic effects. In the cytoplasm the glucocorticoid actions are mediated by a specific receptor (glucocorticoid receptor [GCR]) which has two main isoforms, α and β. Isoform α is the main isoform and can mediate the genomic effects, whereas isoform β is unable to bind glucocorticoid. The nonactivated receptor is complexed with immunophilins (IP) and heat shock proteins (HSP). The glucocorticoid receptor has three exposed domains: the ligand-binding domain (domain A), the DNA-binding domain (domain B), and an immunogenic domain (domain C). Binding of glucocorticoid to domain A causes dissociation of immunophilin and HSP from the receptor. The newly formed complex glucocorticoid–glucocorticoid receptor (GC-GCR) undergoes an allosteric change that allows its translocation to the nucleus. Here, the new complex binds to specific glucocorticoid response elements (GREs) and this binding can either increase the production of anti-inflammatory genes (transactivation) or repress the activity of many important proinflammatory genes by binding to and inhibiting key transcription factors, like NF-κB and activator protein 1, that induce expression of many proinflammatory and vasodilating cytokines (transrepression). Nongenomic effects are mediated by plasma membrane glucocorticoid receptors (mGCR) or by nonspecific interaction with membrane-bound glucocorticoid receptors. There are two types of receptors: the classic glucocorticoid receptor α, that localizes in the plasma membrane, and the nonclassic receptor, with different pharmacologic characteristics. Nongenomic effects may prepare the cell for subsequent glucocorticoid-induced genomic changes, may bridge the gap between the early need of change and the delay in the expression of genomic effects, and may induce specific changes that in some instances are opposite to those induced by genomic effects. GC, glucocorticoid; mGCR, membrane glucocorticoid receptor.