Although kidney stones are common and often cause excruciating pain, there are few options for treatment and a surprising lack of drugs to medicate the condition. In a previous blog post we discussed how a drug that was already being used to treat multiple sclerosis showed promising results for removing painful memories of those who experienced trauma. Now, a new mouse study at the Washington University School of Medicine in St. Louis indicates that a class of drugs which have already been used to treat epilepsy and leukemia potentially could be used to treat kidney stones via epigenetic regulation of microRNAs.
The drugs, known as histone deacetylase (HDAC) inhibitors, could alleviate kidney stones by dissolving them. In their research paper published in Journal of the American Society of Nephrology, scientists discovered that two of these HDAC inhibitors known as trichostatin A and Vorinostat can reduce magnesium and calcium levels in mice urine. These two minerals are crucial to the development of kidney stones in humans.
“We’re hopeful this class of drugs can dissolve kidney stones because its effects on reducing calcium and magnesium are exclusive to kidney cells,” said Jianghui Hou, PhD, senior author and assistant professor of medicine. “In the mice, we achieved dramatic effects at a fraction of the dosage used to treat leukemia and without significant side effects.”
When urine is highly concentrated, magnesium and calcium can crystallize and accumulate which leads to kidney stones. The pain one experiences occurs as a result of the stones blocking the urinary tract and interfering with urine flow. Staying hydrated or avoiding a diet too high in salt can help prevent this from occurring, but some people are genetically predisposed to develop kidney stones and naturally produce urine with higher levels of calcium.
Doctors typically recommend drinking a lot of water in order to alleviate the kidney stone’s passing. A drug known as Thiazide which is used to treat high blood pressure may be prescribed because of its ability to reduce the amount of calcium found in urine. However, it also increases the urine’s levels of magnesium, potentially counteracting its effectiveness in treating kidney stones.
Hou and the research team demonstrated that Vorinostat and trichostatin A mimic a natural process that occurs in the kidney which absorbs magnesium and calcium back into urine. Kidneys filter waste into the urine from the blood and also reclaim crucial minerals that are needed.
In Hou’s previous research, he explained that this process relies heavily on the expression of a gene known as claudin-14. When claudin-14’s activity is idled, the filtering system of the kidney works normally. But when claudin-14 is activated, magnesium and calcium are blocked and cannot re-enter the blood. Two snippets of RNA control the gene’s expression, according to Hou’s previous work.
In their new study, Hou and his team found that trichostatin A and Vorinostat do not act on claudin-14 directly, but mimic micro-RNA molecules and keep the gene’s activity in check. The researchers indicate that the epigenetic regulation of micro-RNAs, which controls gene expression, is a mechanism for handling the levels of calcium in the kidneys. The HDAC inhibitor drugs are attractive as possible kidney stone treatments because of their ability to modify the activity of micro-RNAs.
According to the researchers, “treatment with histone deacetylase (HDAC) inhibitors downregulates renal CLDN14 mRNA and dramatically reduces urinary calcium excretion in mice.” For example, small doses of Vorinostat given to mice reduced the amount of calcium in the urine more than 50 percent and reduced magnesium levels more than 40 percent. They found that trichostatin A had a similar effect.
In addition, “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.”
“Kidney cells were very sensitive to the drug,” Hou explained. “We used one-twentieth of the dose typically used in humans and achieved significant results. We now want to test the drug in clinical trials for patients with kidney stones.”
Mice do not develop kidney stones, so the drugs must be tested against kidney stones in human patients. According to Hau, the new study offers proof of principle, indicating that the same pathway that leads to kidney stones is regulated by HDAC inhibitors.
Source: Learn all about it and read more about their findings here: Gong Y, Himmerkus N, Plain A, Bleich M and Hou J. Epigenetic regulation of microRNAs for controlling CLDN14 expression as a mechanism for renal calcium handling. Journal of the American Society of Nephrology. July 30, 2014.
Reference: Washington University in St. Louis. Potential drug therapy for kidney stones identified in mouse study. September 15, 2014.