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Glucocorticoid activation by 11?-hydroxysteroid dehydrogenase enzymes in relation to inflammation and glycaemic control in chronic kidney disease: A cross-sectional study.

ABSTRACT: OBJECTIVE:Patients with chronic kidney disease (CKD) have dysregulated cortisol metabolism secondary to changes in 11?-hydroxysteroid dehydrogenase (11?-HSD) enzymes. The determinants of this and its clinical implications are poorly defined. METHODS:We performed a cross-sectional study to characterize shifts in cortisol metabolism in relation to renal function, inflammation and glycaemic control. Systemic activation of cortisol by 11?-HSD was measured as the metabolite ratio (tetrahydrocortisol [THF]+5?-tetrahydrocortisol [5?THF])/tetrahydrocortisone (THE) in urine. RESULTS:The cohort included 342 participants with a median age of 63 years, median estimated glomerular filtration rate (eGFR) of 28 mL/min/1.73 m2 and median urine albumin-creatinine ratio of 35.5 mg/mmol. (THF+5?THF)/THE correlated negatively with eGFR (Spearman's ? = -0.116, P = 0.032) and positively with C-reactive protein (? = 0.208, P < 0.001). In multivariable analysis, C-reactive protein remained a significant independent predictor of (THF+5?THF)/THE, but eGFR did not. Elevated (THF+5?THF)/THE was associated with HbA1c (? = 0.144, P = 0.008) and diabetes mellitus (odds ratio for high vs low tertile of (THF+5?THF)/THE 2.57, 95% confidence interval 1.47-4.47). Associations with diabetes mellitus and with HbA1c among the diabetic subgroup were independent of eGFR, C-reactive protein, age, sex and ethnicity. CONCLUSIONS:In summary, glucocorticoid activation by 11?-HSD in our cohort comprising a spectrum of renal function was associated with inflammation and impaired glucose control.

SUBMITTER: Sagmeister MS

PROVIDER: S-EPMC6334281 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Glucocorticoid activation by 11β-hydroxysteroid dehydrogenase enzymes in relation to inflammation and glycaemic control in chronic kidney disease: A cross-sectional study.

Sagmeister Michael S MS Taylor Angela E AE Fenton Anthony A Wall Nadezhda A NA Chanouzas Dimitrios D Nightingale Peter G PG Ferro Charles J CJ Arlt Wiebke W Cockwell Paul P Hardy Rowan S RS Harper Lorraine L

Clinical endocrinology 20181115 1

<h4>Objective</h4>Patients with chronic kidney disease (CKD) have dysregulated cortisol metabolism secondary to changes in 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes. The determinants of this and its clinical implications are poorly defined.<h4>Methods</h4>We performed a cross-sectional study to characterize shifts in cortisol metabolism in relation to renal function, inflammation and glycaemic control. Systemic activation of cortisol by 11β-HSD was measured as the metabolite ratio (tetr ...[more]

PMID: 30358903

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Project description:BackgroundRecent studies have shown that production of cortisol not only takes place in several non-adrenal peripheral tissues such as epithelial cells but, also, the local inter-conversion between cortisone and cortisol is regulated by the 11?-hydroxysteroid dehydrogenases (11?-HSDs). However, little is known about the activity of this non-adrenal glucocorticoid system in cancers.MethodsThe presence of a functioning glucocorticoid system was assessed in human skin squamous cell carcinoma (SCC) and melanoma and further, in 16 epithelial cell lines from 8 different tissue types using ELISA, western blotting and immunofluorescence. 11?-HSD2 was inhibited both pharmacologically and by siRNA technology. Naïve CD8+ T cells were used to test the paracrine effects of cancer-derived cortisol on the immune system in vitro. Functional assays included cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical data of 11?-HSD expression were generated using tissue microarrays of 40 cases of human SCCs as well as a database featuring 315 cancer cases from 15 different tissues.ResultsWe show that cortisol production is a common feature of malignant cells and has paracrine functions. Cortisol production correlated with the magnitude of glucocorticoid receptor (GR)-dependent inhibition of tumour-specific CD8+ T cells in vitro. 11?-HSDs were detectable in human skin SCCs and melanoma. Analyses of publicly available protein expression data of 11?-HSDs demonstrated that 11?-HSD1 and -HSD2 were dysregulated in the majority (73%) of malignancies. Pharmacological manipulation of 11?-HSD2 activity by 18?-glycyrrhetinic acid (GA) and silencing by specific siRNAs modulated the bioavailability of cortisol. Cortisol also acted in an autocrine manner and promoted cell invasion in vitro and cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical analyses using tissue microarrays showed that expression of 11?-HSD2 was significantly reduced in human SCCs of the skin.ConclusionsThe results demonstrate evidence of a cancer-associated glucocorticoid system and show for the first time, the functional significance of cancer-derived cortisol in tumour progression.

Project description:Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11?-hydroxysteroid dehydrogenase type-1 (11?-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11?-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11?-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11?-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11?-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.

Project description:Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11?-Hydroxysteroid dehydrogenase type 1 (11?-HSD1) is a bidirectional GC-activating enzyme that is potently upregulated by inflammation within mesenchymal-derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11?-HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF-Tg) driven by overexpression of tumour necrosis factor (TNF)-? within tissues, including muscle. The inflammatory regulation and functional consequences of 11?-HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11?-HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF-Tg mouse on an 11?-HSD1 null background. 11?-HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF-Tg mice. In human and murine primary myotubes, 11?-HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF-? (mRNA, 7.6-fold, p < 0.005; activity, 4.1-fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11?-HSD1 suppressed proinflammatory cytokine output (interkeukin-6, TNF-?, and interferon-?), but had little impact on markers of muscle wasting in human myotube cultures. TNF-Tg mice on an 11?-11?-HSD1 knockout background developed greater muscle wasting than their TNF-Tg counterparts (27.4% less; p < 0.005), with smaller compacted muscle fibres and increased proinflammatory gene expression relative to TNF-Tg mice with normal 11?-HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11?-HSD1 expression and GC activation within muscle. Although concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNF-?-driven model, local endogenous GC activation appears to be an important anti-inflammatory response that protects against inflammatory muscle wasting in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Dataset Information

Glucocorticoid activation by 11?-hydroxysteroid dehydrogenase enzymes in relation to inflammation and glycaemic control in chronic kidney disease: A cross-sectional study.

Publications

Glucocorticoid activation by 11β-hydroxysteroid dehydrogenase enzymes in relation to inflammation and glycaemic control in chronic kidney disease: A cross-sectional study.

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