January 20, 2021

Fluid-electrolyte homeostasis requires histone deacetylase function

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RS14820 Kelly Hyndman 2Kelly Hyndman, Ph.D., assistant professor in the Division of Nephrology, is the latest winner of the School of Medicine’s Featured Discovery. This initiative celebrates important research from School of Medicine faculty members.

Hyndman’s study, “Fluid-electrolyte homeostasis requires histone deacetylase function,” published in JCI Insight, researched HDAC1 and HDAC2 in the kidney epithelium and maintaining fluid-electrolyte balance during increased dietary sodium intake. Hyndman’s research was collaborative and included colleagues Jennifer Pollock, Ph.D., professor in the Division of Nephrology, and David Pollock, Ph.D., professor in the Division of Nephrology.

On the study, Hyndman says, “We are interested in proteins that control turning genes on and off in the kidney. These proteins are called histone deacetylases, or HDACs. Our kidneys play a necessary role in regulating how much salt and water our bodies need to retain to remain healthy. The goal of this study was to determine if HDACs regulate salt and water retention in the kidneys.”

Hyndman and her team used three approaches in their study:
1. HDAC inhibitors are used in the clinic to treat various cancers. “We looked at the published clinical trials to determine if HDAC inhibitors lead to changes in blood or urine salt and water concentrations,” Hyndman stated.
2. Additionally, “We used laboratory rats and infused HDAC inhibitors directly into the kidney and then challenged the rats with a high salt diet to determine if HDAC inhibitors affected salt and water in the body.”
3. Last, Hyndman explains that they bred mice that lacked HDACs in their kidney and challenged these mice with high salt diets.

Hyndman adds that her team’s findings existed in the clinical data and were confirmed in the rat and mouse data. Here, HDACs play an important role in regulating gene expression in the kidney and they are necessary to remain in salt and water balance. “We concluded that kidney HDACs are a fundamental part of our kidney physiology, and our results help explain why there are clinical reports of salt and water balance disorders with HDAC inhibitor use.”

This work is important to continue understanding of how healthy kidneys work, and can help research-scientists prevent adverse side effects in patients who need to take HDAC inhibitors to treat their cancer in the future. 

The School of Medicine communications staff sat down with Dr. Hyndman to gain insights about the research of this study, UAB, and the science community.

Q: What compelled you to pursue this research?

Our lab group has a long standing interest in determining mechanisms of how the body regulates its salt and water balance. The kidneys are necessary to regulate how much salt and water is kept in our body, in response to what we eat, drink, how active we are, etc. Over the past few decades it has become clear that certain genes are turned on or off depending on changes in our environment, like eating a big salty meal. A group of proteins called, histone deacetylases (HDACs), play a role in regulating turning genes on and off. It turns out, our kidneys express many different HDACs, and so our goal was to determine what their function is in the kidney. We asked: is it related to regulation salt and water?

Q: What was your most unexpected finding?

With our 3 different approaches—clinical data, pharmacological inhibition in the rat, and genetic deletion of HDACs in the mouse kidney—I was very surprised to see that, in all three models, increases in urination and changes in plasma salts were conserved. This suggests that HDACs play a very important role in regulating these pathways. What was quite unexpected was we found that HDAC inhibitors (either in the clinical data or the rat data) lead to changes in blood pressure. However, this was not true in the mice that lacked kidney HDACs—their blood pressures remained normal. We need to study this further.

Q: How do you feel your research will impact the science community?

Our study helps us to further understand how kidneys work (the physiology of the system). Once we know what their function is in a healthy kidney, we can then ask new questions about potential derangements of these proteins in disease states, like acute or chronic kidney disease. Our data also helps explain adverse side effects that may be experienced by patients, thus helping doctors understand potential risks and how they can try to mitigate them.

Q: What is your research’s relevance to human disease?

There are six HDAC inhibitors currently FDA approved to treat neurological disorders and certain cancers. These are first generation inhibitors and have some adverse events, like leading to salt and water balance issues. Our study highlights why HDAC inhibitors may lead to these unintended events; HDAC activity in the kidney helps control salt and water in the body. There are many pharmaceutical companies developing next generation HDAC inhibitors, and many ongoing clinical trials, so hopefully we can help more cancer patients with fewer adverse events. There is also this idea that maybe HDAC inhibitors could treat other disease, like kidney diseases, so our data highlights important functions of kidney HDACs that need to be considered.

Q: When did you know you had an important discovery?

When we analyzed the clinical data set and it matched nicely to the rat and mice data, it felt like a very important discovery. To have significant events like increased urination frequency and changes in plasma sodium be conserved among these different interventions really suggested this was an important finding. Our approach was very much a bench to bedside, and maybe back to bench again!

Q: How has being at UAB and living in Birmingham affected your research?

The Division of Nephrology is an outstanding part of UAB where basic scientists like myself regularly interact with the clinical researchers and physicians. Having a diverse group of individuals with all different strengths to discuss our data, especially the clinical dataset, really elevated this project.

Q: What made you come to UAB?

I was lucky enough to have finished my postdoctoral fellowship with Dr. Jennifer Pollock right when she and Dr. David Pollock were recruited to UAB. It was the perfect time to start my faculty position, but yet still collaborate with a dynamic team of very talented kidney physiologists and biochemists who I had worked with for the past five years. The Division of Nephrology has an outstanding reputation and I am very proud to be part of the team here.

Q: What do you find makes the science community here (at UAB) unique?

Bench to Beside, Beside to Bench is really embraced here at UAB, and especially in the Division of Nephrology. Being able to see how the mechanisms we are defining by using model organisms relates to human health, and having that appreciated, encouraged, and supported makes the scientific community very unique.

Read the publication here.