endothelin-1 and Hypercalcemia

Alterations in bone architecture and mineral metabolism are common complications of malignancy. Cancers such as breast, prostate, and lung can affect the skeleton either indirectly through the elaboration of factors that act to disrupt normal calcium homeostasis at the level of the kidney and bone; or directly via secondary spread of tumor to bone. Although the pathophysiology of these skeletal complications is diverse, it is clear that the osteoclast and osteoblast are not just bystanders but are active participants in the development and progression of hypercalcemia and bone metastasis. Our understanding of the molecular mechanisms of metastasis leading to tumor cell escape, homing, adhesion, and secondary growth in a hospitable environment are evolving. Treatment modalities aimed at not only reducing tumor burden but altering the skeletal response to tumor have shown benefit. Newer generation bisphosphonates are quite effective in controlling hypercalcemia of malignancy and have been shown to delay progression of skeletal metastases. Clearly, cancer-associated bone morbidity remains a major public health problem. To improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review will detail scientific advances regarding this area.

Topics: Animals; Atrasentan; Bone Neoplasms; Cell Adhesion Molecules; Cytokines; Diphosphonates; Endothelin-1; Female; Gene Expression Regulation, Neoplastic; Humans; Hypercalcemia; Immunotherapy; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Nude; Neoplasm Proteins; Osteoblasts; Osteolysis; Pain; Pain Management; Pyrrolidines; Xenograft Model Antitumor Assays

Hypercalcaemia can occur under various pathological conditions, such as primary hyperparathyroidism, malignancy or granulomatosis, and it induces natriuresis and polyuria in various species via an unknown mechanism. A previous study demonstrated that hypercalcaemia induced by vitamin D in rats increased endothelin (ET)-1 expression in the distal nephron, which suggests the involvement of the ET system in hypercalcaemia-induced effects. In the present study, we demonstrate that, during vitamin D-induced hypercalcaemia, the activation of ET system by increased ET-1 is responsible for natriuresis but not for polyuria. Vitamin D-treated hypercalcaemic mice showed a blunted response to amiloride, suggesting that epithelial sodium channel function is inhibited. We have identified an original pathway that specifically mediates the effects of vitamin D-induced hypercalcaemia on sodium handling in the distal nephron without affecting water handling.. Acute hypercalcaemia increases urinary sodium and water excretion; however, the underlying molecular mechanism remains unclear. Because vitamin D-induced hypercalcaemia increases the renal expression of endothelin (ET)-1, we hypothesized that ET-1 mediates the effects of hypercalcaemia on renal sodium and water handling. Hypercalcaemia was induced in 8-week-old, parathyroid hormone-supplemented, male mice by oral administration of dihydrotachysterol (DHT) for 3 days. DHT-treated mice became hypercalcaemic and displayed increased urinary water and sodium excretion compared to controls. mRNA levels of ET-1 and the transcription factors CCAAT-enhancer binding protein β and δ were specifically increased in the distal convoluted tubule and downstream segments in DHT-treated mice. To examine the role of the ET system in hypercalcaemia-induced natriuresis and polyuria, mice were treated with the ET-1 receptor antagonist macitentan, with or without DHT. Mice treated with both macitentan and DHT displayed hypercalcaemia and polyuria similar to that in mice treated with DHT alone; however, no increase in urinary sodium excretion was observed. To identify the affected sodium transport mechanism, we assessed the response to various diuretics in control and DHT-treated hypercalcaemic mice. Amiloride, an inhibitor of the epithelial sodium channel (ENaC), increased sodium excretion to a lesser extent in DHT-treated mice compared to control mice. Mice treated with either macitentan+DHT or macitentan alone had a similar response to amiloride. In summary, vitamin D-induced hypercalcaemia increases the renal production of ET-1 and decreases ENaC activity, which is probably responsible for the rise in urinary sodium excretion but not for polyuria.

Topics: Acute Disease; Animals; Cell Line, Transformed; Endothelin-1; Hypercalcemia; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Natriuresis; Polyuria; Vitamin D

Topics: Calcium; Endothelin-1; Humans; Hypercalcemia; Sodium

Although hypercalcemia causes diuresis and natriuresis, the molecular mechanisms of these effects are not well established. Recently, the important role of the calcium-sensing receptor (CaR) in hypercalcemia-induced polyuria was reported. Endothelin-1 (ET-1) that is locally produced in the nephron has been suggested to have the natriuretic and/or diuretic effects in the kidney. Therefore, we hypothesized that ET-1 expression could be increased through the activation of CaR in the kidney in hypercalcemia.. Rats were made hypercalcemic by dihydrotachysterol (DHT) treatment. The urinary concentration of ET-1 and the mRNA expression of ET-1 in the kidney were determined. Immunohistochemistry was performed to determine types of the cells that produce ET-1. CaR and ET-1 promoter luciferase constructs were co-expressed in COS-7 cells and the ET-1 promoter activity following the addition of extracellular calcium was measured by the luciferase assay.. In hypercalcemic rat, urinary ET-1 excretion was increased by twofold, and ET-1 mRNA expression was increased in the kidney cortex by threefold. In cortical collecting duct (CCD), both principal cells and intercalated cells synthesized ET-1. In cells that express CaR, ET-1 promoter was activated in a dose-dependent manner by extracellular calcium over the range of 0.5 to 3.0 mmol/L.. First, activation of CaR increases ET-1 transcription in a dose-dependent manner. Second, hypercalcemia increases ET-1 production in the kidney cortex. These data suggest the possibility that CaR might play an important role in hypercalcemia-induced increase in ET-1 production.

Topics: Animals; COS Cells; Disease Models, Animal; Diuresis; Endothelin-1; Gene Expression Regulation; Hypercalcemia; Immunohistochemistry; Kidney Cortex; Male; Promoter Regions, Genetic; Rats; Rats, Wistar; Receptors, Calcium-Sensing; RNA, Messenger

The authors study mechanisms of nephrotoxic action of high-osmolar radiopaque substance (RPS) and the role of endothelin-1, hormonal endothelial factor, in these mechanisms in patients with different variants of chronic glomerulonephritis. Endothelin-1 is a potent endogenic vasoconstrictor participating in regulation of intrarenal hemodynamics and renal function the synthesis of which id related to Ca metabolism. Mechanisms of nephrotoxic action of RPS involve disturbances of Ca metabolism (hypercalcemia), high concentration of blood endothelin-1 which directly correlated with baseline creatinine in the serum and deterioration of renal function after RPS introduction. Ca ions antagonists (corinfar) contribute to prevention of changes in endothelin-1 synthesis relevant renal dysfunction induced by RPS.

Topics: Acute Kidney Injury; Adolescent; Adult; Calcium; Calcium Channel Blockers; Contrast Media; Creatinine; Diatrizoate Meglumine; Endothelin-1; Female; Humans; Hypercalcemia; Kidney; Male; Middle Aged; Nifedipine; Time Factors