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Research Article Free access | 10.1172/JCI117212

Chronic hypocalcemia of vitamin D deficiency leads to lower intracellular calcium concentrations in rat hepatocytes.

M Gascon-Barré, P Haddad, S J Provencher, S Bilodeau, F Pecker, S Lotersztajn, and S Vallières

Centre de Recherche Clinique André-Viallet, Hôpital Saint-Luc, Montreal, Canada.

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Centre de Recherche Clinique André-Viallet, Hôpital Saint-Luc, Montreal, Canada.

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Centre de Recherche Clinique André-Viallet, Hôpital Saint-Luc, Montreal, Canada.

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Centre de Recherche Clinique André-Viallet, Hôpital Saint-Luc, Montreal, Canada.

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Centre de Recherche Clinique André-Viallet, Hôpital Saint-Luc, Montreal, Canada.

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Centre de Recherche Clinique André-Viallet, Hôpital Saint-Luc, Montreal, Canada.

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Centre de Recherche Clinique André-Viallet, Hôpital Saint-Luc, Montreal, Canada.

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Published May 1, 1994 - More info

Published in Volume 93, Issue 5 on May 1, 1994
J Clin Invest. 1994;93(5):2159–2167. https://doi.org/10.1172/JCI117212.
© 1994 The American Society for Clinical Investigation
Published May 1, 1994 - Version history
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Abstract

Several lines of evidence indicate that calcium deficiency is associated with cellular defects in many tissues and organs. Owing to the large in vivo gradient between ionized extra- and intracellular Ca2+ concentrations ([Ca2+]i), it is generally recognized that the prevailing circulating Ca2+ does not significantly affect resting cytosolic Ca2+. To probe the consequences of hypocalcemia on [Ca2+]i, a model of chronic hypocalcemia secondary to vitamin D (D) deficiency was used. Hepatocytes were isolated from livers of hypocalcemic D-deficient, of normocalcemic D3-repleted, or of normal control rats presenting serum Ca2+ of 0.78 +/- 0.02, 1.24 +/- 0.03, or 1.25 +/- 0.01 mM, respectively (P < 0.0001). [Ca2+]i was measured in cell couplets using the fluorescent probe Fura-2. Hepatocytes of normocalcemic D3-repleted and of normal controls exhibited similar [Ca2+]i of 227 +/- 10 and 242 +/- 9 nM, respectively (NS), whereas those of hypocalcemic rats had significantly lower resting [Ca2+]i (172 +/- 10 nM; P < 0.0003). Stimulation of hepatocytes with the alpha 1-adrenoreceptor agonist phenylephrine illicited increases in cytosolic Ca2+ leading to similar [Ca2+]i and phosphorylase a (a Ca(2+)-dependent enzyme) activity in all groups but in contrast to normocalcemia, low extracellular Ca2+ was often accompanied by a rapid decay in the sustained phase of the [Ca2+]i response. When stimulated with the powerful hepatic mitogen epidermal growth factor (EGF), hepatocytes isolated from hypocalcemic rat livers responded with a blunted maximal [Ca2+]i of 237.6 +/- 18.7 compared with 605.2 +/- 89.9 nM (P < 0.0001) for their normal counterparts, while the EGF-mediated DNA synthesis response was reduced by 50% by the hypocalcemic condition (P < 0.03). Further studies on the possible mechanisms involved in the perturbed [Ca2+]i homeostasis associated with chronic hypocalcemia revealed the presence of an unchanged plasma membrane Ca2+ ATPase but of a significant decrease in agonist-stimulated Ca2+ entry as indicated using Mn2+ as surrogate ion (P < 0.03). Our data, thus indicate that, in rat hepatocytes, the in vivo calcium status significantly affects resting [Ca2+]i, and from this we raise the hypothesis that this lower than normal [Ca2+]i may be linked, in calcium disorders, to inappropriate cell responses mediated through the calcium signaling pathway as illustrated by the response to phenylephrine and EGF.

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