Human from fish – flipping the salt regulation switch

Researchers have made an evolution related breakthrough in discovering the critical change in hormonal salt regulation that allowed life to evolve out of the seas and onto land.

In his paper published in the Proceedings of the National Academy of Sciences, Hudson Institute’s Professor Peter Fuller and his research team, with collaborators from La Trobe University, found that a single amino acid change in a salt regulation receptor (the mineralocorticoid receptor) enabled the receptor to form a critical system that retains salt in the kidney. This system is operational in terrestrial creatures from amphibians to man.

The novel finding came as part of a wider body of research looking into steroid receptors to treat salt retention in cases of high blood pressure and heart failure. The discovery provides insight into how steroid receptors function, and has implications for future drug design.

The importance of salt

Prof Fuller said, “Salt is incredibly important. It is essential for animals with a vascular system as it ensures they a maintain a healthy blood pressure.

“In evolutionary terms, when life emerged from the primordial ooze and onto land, migrating from a water-based environment to a land-based environment, one of the critical things that these creatures needed to do to survive was to retain salt. Outside of a salty environment, salt losses increase and survival is challenged,” he said.

What changed?

“Both fish and land-based vertebrates have the mineralocorticoid receptor, which regulates salt retention. The very unusual thing about this receptor is that it serves a different functionality in a fish than in a human.

“For example, in fish when a particular steroid hormone (progesterone) is present it turns on the mineralocorticoid receptor to retain salt but in humans it blocks the receptor, which may result in salt loss.

“This is a mystifying response. Why does this receptor in fish and humans, which is very similar by many criteria, have such an opposite response to this hormone depending on the organism it belongs to?

“We wanted to find out what the difference was in this receptor when comparing it between land vertebrates and fish,” he said.

The researchers analysed and compared the mineralocorticoid receptors of zebrafish and humans to pinpoint where change took place. Their research involved creating hybrid receptors that were part zebrafish, part human, to find the region in the receptor responsible for this switch in function.

Through this approach they were able to locate the amino acid change in the receptor that was responsible for this complete change in functionality.

Implications for future therapeutic drugs

Prof Fuller said, “In humans, if we inappropriately retain salt it leads to high blood pressure, which can result in cardiac failure. Improving our knowledge of the mineralocorticoid receptor will help further our understanding of therapeutic treatments for sodium-related disease.

“This study also changes the way we think about designing drugs to block steroid hormone receptors. We show that drug companies could look for other interactions within the receptors that they could target.”

A tiny change with big consequences

Prof Fuller said, “The thing that was striking was that it was only one tiny change. If you changed one amino acid in the receptor (from leucine or threonine or vice versa), it reacted in the opposite way.

“It’s significant that such a tiny change in one place on this one receptor contributed to a profound evolutionary chain of events that resulted in terrestrial life,” he said.