Endocrine Abstracts

Bile acids (BAs) are synthesised from cholesterol in the liver and promote lipid digestion. An emerging body of evidence, however, suggests that BAs are also key signaling molecules with potent metabolic and endocrine functions, exerting their effects through activation of BA receptors, including the farnesoid-X- (FXR) and the G-protein-coupled- (TGR5) receptors. Disturbed BA synthesis has been associated with type 2 diabetes mellitus and insulin resistance, and recent studies...

The 5-reductases are steroid metabolising enzymes that saturate the C4=C5 bond of the steroid A-ring, and their substrates include androgens, glucocorticoids, and bile acids. 5β-reductases (SRD5A1 & SRD5A2) convert testosterone to the more potent androgen 5β-dihydrotestosterone, and carry out the first step in glucocorticoid clearance, generating 5β-dihydrocortisol from cortisol. 5β-reductase (AKR1D1) is also able to carry out the first step of glucocor...

Receptor-mediated endocytosis (RME), involving megalin and cubilin, mediates renal proximal-tubular reabsorption of glucose, proteins and hormones including insulin, parathyroid-hormone and vitamin D. RME disruption occurs in Dent’s disease patients with mutations of the chloride/proton antiporter, CLC-5, who suffer from low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis and renal failure. To further investigate the RME role of CLC-5 we established conditio...

Inbred laboratory mice are widely used to generate, by homologous recombination, transgenic and chemical mutagenesis routes, genetic models of human disease. However, physiological studies of such models are hampered by the lack of normal ranges for serum and urinary biochemistry, particularly in relation to acclimatisation following placement in metabolic cages. To establish such values, we investigated urinary and serum parameters in forty, 24–30 week-old C3H/HeH, BALB/...

Renal stone disease is a common disorder for which the underlying causes remain largely unknown. We have investigated a hereditary renal calcification mouse model, Rcalc1, that is not associated with hypercalciuria for underlying mechanisms. Kidney RNA from 30 to 33 week-old Rcalc1 and control BALB/c and C3H female mice (n=4/group) was extracted and hybridised to Mouse Genome 430 2.0 arrays (Affymetrix). Following Robust Multichip Average normalization, pair-wise compar...

Transient receptor potential cation channel, subfamily Vanilloid, member 5 (TRPV5) is a member of the TRP superfamily. TRPV5, which functions as a tetramer, is localized to apical membranes of distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, and is involved in vitamin D-regulated calcium reabsorption. Mice with a targeted deletion of Trpv5 (Trpv5−/−) develop severe hypercalciuria, compensatory hyperabsorption of dietary ...

Abnormalities of calcium homeostasis such as secondary or tertiary hyperparathyroidism, and renal osteodystrophy often occur in patients with kidney failure. However, investigations of the underlying molecular mechanisms have been hampered by the lack of available tissues from patients and the lack of suitable animal models. We therefore sought to overcome this limitation by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea and identified...

Vascular calcification, occurring in organs such as heart and kidneys, is associated with increased risk of cardiovascular mortality. The underlying molecular mechanisms remain unknown. To elucidate these, we investigated C3H mice, an inbred strain susceptible to vascular, myocardial and renal calcification. Myocardial calcification in C3H mice involves 4 genetic loci, Dyscalc1-4, that map to chromosomes 7, 4, 12 and 14, respectively. Dyscalc1 contributes to myoc...

Renal calcification (nephrocalcinosis), which has a multi-factorial etiology involving environmental and genetic determinants, affects ~8% of adults by 70 years. Nephrocalcinosis may occur as a familial disorder in ~65% of patients, and in 70% of patients, nephrocalcinosis may be associated with endocrine and metabolic disorders that include primary hyperparathyroidism, renal tubular acidosis, hypercalciuria, cystinuria, and hyperoxaluria. Investigations of families with hered...

Endocrine cells utilise endocytosis to scavenge polypeptide hormones, and to generate signals from inactive precursors, such as release of thyroid hormones from thyroglobulin in thyrocytes, and activation of vitamin D after reabsorption of ultrafiltrated pro-vitamin D binding protein complex by renal proximal tubular cells (PTC). We have investigated the role of CLC-5, a chloride/proton antiporter expressed in apical endosomes and the apical plasma membrane of thyrocytes and P...