Effect of glucocorticoids on bone metabolism in replacement therapy of adrenal insufficiency. Literature review

Adrenal insufficiency (AI) is a syndrome caused by disturbance in the synthesis and secretion of hormones of the adrenal cortex, which ensure the vital activity, energy and water-salt homeostasis. The widest hormonal deficiency is observed in primary hypocorticism, when the synthesis of not only glucocorticoids (GC) and adrenal androgens, but also mineralocorticoids is disrupted. Lifelong replacement therapy with GCs for this pathology may be associated with a risk of bone loss and osteoporosis. However, at present, there are no clear guidelines for diagnosis of bone condition, including and bone mineral density (BMD) monitoring during treatment with GCs in patients with AI. This review summarizes collected data on the key pathogenetic links of glucocorticoid-induced osteoporosis, incidence of decreased BMD and fractures in patients with AI. In this review factors that influence bone metabolism in this cohort of patients are considered: the type and the dose of prescribed GCs, the type (primary, secondary, HH in congenital adrenal cortex dysfunction) and the duration of AI, age, gender, and the presence of concomitant endocrine disorders (hypogonadism, growth hormone (GH) deficiency). In addition, the review presents data on the effect of adrenal androgen replacement therapy and recombinant GH therapy on bone metabolism in secondary AI.

Gene Copy Number Variation Does Not Reflect Structure or Environmental Selection in Two Recently Diverged California Populations of Suillus brevipes

Gene copy number variation across individuals has been shown to track population structure and be a source of adaptive genetic variation with significant fitness impacts. In this study, we report opposite results for both predictions based on the analysis of gene copy number variants (CNVs) of Suillus brevipes, a mycorrhizal fungus adapted to coastal and montane habitats in California. In order to assess whether gene copy number variation mirrored population structure and selection in this species, we investigated two previously studied locally adapted populations showing a highly differentiated genomic region encompassing a gene predicted to confer salt tolerance. In addition, we examined whether copy number in the genes related to salt homeostasis was differentiated between the two populations. Although we found many instances of CNV regions across the genomes of S. brevipes individuals, we also found CNVs did not recover population structure and known salt-tolerance-related genes were not under selection across the coastal population. Our results contrast with predictions of CNVs matching single-nucleotide polymorphism divergence and showed CNVs of genes for salt homeostasis are not under selection in S. brevipes.

Regulation of Electrolyte Permeability by Herbal Monomers in Edematous Disorders

: Edema is a gradually accumulation of fluid in the interstitial tissues or luminal cavities, which is regulated by ion transport pathways and reflects a dysfunction of fluid and salt homeostasis. Increasing evidence suggests that some herbal monomers significantly reduce organ/tissue edema. In this review, we briefly summarized the electrolyte permeability involved in pathomechanisms of organ edema, and the benefits of herbal monomers on ionic transport machinery, including Na+ -K+ -ATPase, Na+ and Clchannels, Na+ -K+ -2Clco-transporter, etc. The pharmaceutical relevance is implicated for developing advanced strategies to mitigate edematous disorders. In conclusion, the natural herbal monomers regulate electrolyte permeability in many edematous disorders, and further basic and clinical studies are needed.

Critical role of WNK1 in MYC-dependent early thymocyte development

WNK1, a kinase that controls kidney salt homeostasis, also regulates adhesion and migration in CD4+ T cells. Wnk1 is highly expressed in thymocytes, and since migration is important for thymocyte maturation, we investigated a role for WNK1 in thymocyte development. We find that WNK1 is required for the transition of double negative (DN) thymocytes through the β-selection checkpoint and subsequent proliferation and differentiation into double positive (DP) thymocytes. Furthermore, we show that WNK1 negatively regulates LFA1-mediated adhesion and positively regulates CXCL12-induced migration in DN thymocytes. Despite this, migration defects of WNK1-deficient thymocytes do not account for the developmental arrest. Instead, we show that in DN thymocytes WNK1 transduces pre-TCR signals via OXSR1 and STK39 kinases and the SLC12A2 ion co-transporter that are required for post-transcriptional upregulation of MYC and subsequent proliferation and differentiation into DP thymocytes. Thus, a pathway regulating ion homeostasis is a critical regulator of thymocyte development.

Dietary sodium modulates nephropathy in Nedd4-2-deficient mice

Salt homeostasis is maintained by tight control of Na+ filtration and reabsorption. In the distal part of the nephron the ubiquitin protein ligase Nedd4-2 regulates membrane abundance and thus activity of the epithelial Na+ channel (ENaC), which is rate-limiting for Na+ reabsorption. Nedd4-2 deficiency in mouse results in elevated ENaC and nephropathy, however the contribution of dietary salt to this has not been characterized. In this study we show that high dietary Na+ exacerbated kidney injury in Nedd4-2-deficient mice, significantly perturbing normal postnatal nephrogenesis and resulting in multifocal areas of renal dysplasia, increased markers of kidney injury and a decline in renal function. In control mice, high dietary Na+ resulted in reduced levels of ENaC. However, Nedd4-2-deficient kidneys maintained elevated ENaC even after high dietary Na+, suggesting that the inability to efficiently downregulate ENaC is responsible for the salt-sensitivity of disease. Importantly, low dietary Na+ significantly ameliorated nephropathy in Nedd4-2-deficient mice. Our results demonstrate that due to dysregulation of ENaC, kidney injury in Nedd4-2-deficient mice is sensitive to dietary Na+, which may have implications in the management of disease in patients with kidney disease.