HDAC inhibitors may dissolve kidney stones

Here[1] is the latest review on HDAC inhibitors in Nature Reviews Drug Discovery. The authors highlight the development of HDAC inhibitors and their use in cancers, neurodegenerative diseases, neuropsychiatric disorders, inflammatory diseases, and virus infections. However, they have missed a recent use —- treatment of kidney stones.

A recent paper[2] reported that HDAC inhibitors such as trichostatin A (TsA) and vorinostat (SAHA) could lower levels of calcium and magnesium in the urine. This process is dependent on claudin-14, a negative regulator of calcium reabsorption in the kidney.

Claudin-14 is naturally silenced by miR-9 and miR-374 which are transcriptionally regulated by HDAC. HDAC inhibitors stimulate the transcription of miR-9 and miR-374, repressing the expression of claudin-14. A single dose of SAHA at 25 mg/kg significantly reduces claudin-14 mRNA levels in the kidney by 56%. TsA is more effective than SAHA. However, it is not know which specific HDAC member mediates these effects.

SAHA at 5 mg/kg significantly reduces the urinary excretion of calcium and magnesium by 47% and 40%, respectively. The FDA has approved SAHA for the treatment of CTCL at a dosage of 400 mg once daily. Because SAHA reduces urine calcium level at an extremely low dosage (about 1/20), adverse events can be reduced.

Patients with autosomal dominant hypocalcemia (ADH) naturally repress the transcription of miR-9 and miR-374 and release too much calcium into the urine. They are genetically prone to developing kidney stones. HDAC inhibitors may be particularly effective for patients with ADH.

Mice don’t develop kidney stones, what a pity. What confuse me is that no abnormality in serum or urine calcium level has been reported for SAHA. Are there any other secrets? Dr. Jianghui Hou says[3] they want to test the drug in clinical trials for patients with kidney stones. It’s worth expecting.

[1] Nat Rev drug discov. 2014, doi:10.1038/nrd4360.

[2] J Am Soc Nephrol. 2014, doi: 10.1681/ASN.2014020129.

[3] Potential drug therapy for kidney stones identified in mouse study.



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