MedicalResearch.com Interview with:
Matthew Bailey PhD
Faculty Principal Investigator
British Heart Foundation Centre for Cardiovascular Science
The University of Edinburgh, Edinburgh, United Kingdom.
MedicalResearch.com: What is the background for this study?
Dr. Bailey: This study started with our interest in salt homeostasis and long term blood pressure, so it’s firmly rooted in the cardiovascular/renal disease risk factor arena. We were interested in salt-sensitivity- why does blood pressure go up in some people when they eat salt but not in others. I’m a renal physiologist, so we had a number of papers looking at renal salt excretion and blood pressure. We initially used a gene targeting approach to remove a gene (Hsd11b2) which acts as a suppressor of the mineralocorticoid pathway. It’s mainly expressed in the kidney and when we deleted the gene throughout the body we saw a number of renal abnormalities all associated with high mineralocorticoid activity. This was consistent with the “hypertension follows the kidney” theory of blood pressure control. There is a human disease called “Apparent Mineralocorticoid Excess”- there are people do not have the gene and are thought to have renal hypertension. Our study threw up some anomalies which we couldn’t easily interpret but suggested that the brain was involved. We moved to a more refined technology that allowed us to knockout a gene in one organ system but not another. We knew the gene was in the brain and localized to a very restricted subset of neurons linked to salt-appetite and blood pressure control. Previous studies had shown that these neurons were activated in salt-depleted rats (ie rats that needed to eat salt). We started there but didn’t anticipate that the effect on salt hunger and on blood pressure would be so large because renal function is -as far as we can tell- normal.
MedicalResearch.com: What are the main findings?
Dr. Bailey: The main findings are these: removing this gene in a small number of nerve cells in the brain stem has two large effect:
- It turns on a strong salt appetite that is abnormal- it is not driven by any physiological need. The increased salt intake causes blood pressure to rise sharply and the hypertension persists for as long as the high salt intake is maintained. Blood pressure can be normalized when salt intake is lowered. The high blood pressure is not due to keeping salt in the body- this is all excreted by the kidney. It reflects a change in blood vessel contraction and also a change in autonomic control of heart rate.
- A very important finding was that control mice do not response this way to salt. This tells us that removing this single gene to turn on the mineralocortioid pathway in a few brain cells induces a hunger for salt and changes the way that the brain responds to salt causing hypertension.
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Bailey: Great question- this is fundamental science defining basic physiological processes but societal implications are interesting- the UK has a recommended salt intake of 6g per day but the population eats 8.5g per day. (Similar in the USA and most other nations that I’ve looked at.) The WHO recommends 5g per day, so we are all habitually eating too much salt. Unlocking the pathways in the brain that control our hunger for salt will help us understand better our relationship with the food we eat. In a broad context, the same pathways that control salt hunger in the brain are controlling salt taste by the tongue, salt uptake from food by the gut and salt excretion by the kidney. This makes evolutionary sense but the environment has changed- salt isn’t scarce anymore and gain-of function mutations can give us multiple hits for salt induced hypertension.
Specific clinical implications are for certain patients groups (heart failure, kidney failure) that have to reduce salt intake but find it very hard to do. We found in our study that we could manage salt intake in the mice by giving them a daily oral dose of spironolactone, a mineralocorticoid antagonist. Certain patient groups (heart failure for example) are advised to lower salt intake but compliance is poor. Spironolactone is already widely used in humans and is cheap ( less than 0.50 USD per day). It could be used to help certain patient groups control salt intake as part of their clinical management.
MedicalResearch.com: Is there anything else you would like to add?
Dr. Bailey: We were funded by research charities- the British Heart Foundation and Kidney Research UK.
Circulation. 2016 Mar 7. pii: CIRCULATIONAHA.115.019341. [Epub ahead of print]
Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension.
Evans LC1, Ivy JR1, Wyrwoll C1, McNairn JA1, Menzies RI1, Christensen TH1, Al-Dujaili EA2, Kenyon CJ1, Mullins JJ1, Seckl JR1, Holmes MC1, Bailey MA3.