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PTH regulates expression of ClC-5 chloride channel in the kidney
I V Silva1, C J Blaisdell, S E Guggino
1Eudowood Division of Respiratory Sciences, The Johns Hopkins School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
Abstract:
Mutations in the chloride channel, ClC-5, have been described in several inherited diseases that result in the formation of kidney stones. To determine whether ClC-5 is also involved in calcium homeostasis, we investigated whether ClC-5 mRNA and protein expression are modulated in rats deficient in 1alpha,25(OH)(2) vitamin D(3) with and without thyroparathyroidectomy. Parathyroid hormone (PTH) was replaced in some animals. Vitamin D-deficient, thyroparathyrodectomized rats had lower serum and higher urinary calcium concentrations compared with control animals as well as lower serum PTH and calcitonin concentrations. ClC-5 mRNA and protein levels in the cortex decrease in vitamin D-deficient, thyroparathyroidectomized rats compared with both control and vitamin D-deficient animals. ClC-5 mRNA and protein expression increase near to control levels in vitamin D-deficient, thyroparathyroidectomized rats injected with PTH. No significant changes in ClC-5 mRNA and protein expression in the medulla were detected in any experimental group. Our results suggest that PTH modulates the expression of ClC-5 in the kidney cortex and that neither 1alpha,25(OH)(2) vitamin D(3) nor PTH regulates ClC-5 expression in the medulla. The pattern of expression of ClC-5 varies with urinary calcium. Animals with higher urinary calcium concentrations have lower levels of ClC-5 mRNA and protein expression, suggesting that the ClC-5 chloride channel plays a role in calcium reabsorption.
Insights
Parathyroid hormone (PTH) influences the expression of the ClC-5 chloride channel in rat kidney cortex. Lower ClC-5 levels correlate with higher urinary calcium, suggesting a role in calcium reabsorption.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Mutations in the chloride channel ClC-5 are linked to inherited kidney stone diseases.
- The role of ClC-5 in calcium homeostasis remains unclear.
- Vitamin D and parathyroid hormone (PTH) are key regulators of calcium metabolism.
Purpose of the Study:
- To investigate the modulation of ClC-5 mRNA and protein expression in vitamin D-deficient rats.
- To determine the influence of thyroparathyroidectomy and PTH replacement on ClC-5 expression.
- To explore the relationship between ClC-5 expression and calcium homeostasis.
Main Methods:
- Studied ClC-5 mRNA and protein expression in vitamin D-deficient rats with and without thyroparathyroidectomy.
- Administered PTH replacement to a subset of experimental animals.
- Measured serum and urinary calcium, PTH, and calcitonin levels.
Main Results:
- Vitamin D-deficient, thyroparathyroidectomized rats exhibited lower serum and higher urinary calcium.
- ClC-5 mRNA and protein levels decreased in the kidney cortex of these rats.
- PTH administration normalized ClC-5 expression in the cortex.
- No significant changes in medullary ClC-5 expression were observed.
- Higher urinary calcium correlated with lower ClC-5 expression.
Conclusions:
- PTH modulates ClC-5 expression in the kidney cortex.
- Neither vitamin D nor PTH regulates ClC-5 expression in the kidney medulla.
- ClC-5 chloride channel activity is associated with renal calcium reabsorption.