The kidney has a major role in extracellular
calcium homeostasis. Multiple genetic linkage and association studies identified three tight junction genes from the kidney--claudin-14, -16, and -19--as critical for
calcium imbalance diseases. Despite the compelling
biologic evidence that the
claudin-14/16/19
proteins form a regulated paracellular pathway for
calcium reabsorption, approaches to regulate this transport pathway are largely unavailable, hindering the development of
therapies to correct
calcium transport abnormalities. Here, we report that treatment with
histone deacetylase (
HDAC) inhibitors downregulates renal CLDN14
mRNA and dramatically reduces urinary
calcium excretion in mice. Furthermore, treatment of mice with
HDAC inhibitors stimulated the transcription of renal microRNA-9 (miR-9) and miR-374 genes, which have been shown to repress the expression of
claudin-14, the negative regulator of the paracellular pathway. With renal clearance and tubule perfusion techniques, we showed that
HDAC inhibitors transiently increase the paracellular
cation conductance in the thick ascending limb. Genetic ablation of
claudin-14 or the use of a loop
diuretic in mice abrogated
HDAC inhibitor-induced hypocalciuria. The genetic mutations in the
calcium-sensing receptor from patients with autosomal dominant
hypocalcemia (ADH) repressed the transcription of miR-9 and miR-374 genes, and treatment with an
HDAC inhibitor rescued the phenotypes of cell and animal models of ADH. Furthermore, systemic treatment of mice with
antagomiRs against these miRs relieved
claudin-14 gene silencing and caused an ADH-like phenotype. Together, our findings provide proof of concept for a novel therapeutic principle on the basis of epigenetic regulation of renal miRs to treat hypercalciuric diseases.