July 13, 2016
By Greg Peters
|Lei Pei and Alan Yu|
For the past 15 years, Alan Yu, M.B., B. Chir., director of the KU Kidney Institute at the University of Kansas Medical Center, has been immersed in a complex scientific world filled with paracellular transport, tight junctions and claudins.
Yu and his research team have spent years drilling down into the granular world of how our kidneys perform at the cellular level. What they have discovered is that something called paracellular transport is a key to how efficiently the kidneys use energy to keep us alive.
Why is this important? Gram for gram, kidneys are one of the biggest energy consumers in the body. And if a person's kidneys aren't working efficiently, they risk developing a serious condition called ischemia from a lack of oxygen, which could lead to death.
Yu's latest kidney research has been published in the prestigious Journal of Clinical Investigation - the official publication of the American Society of Clinical Investigation. This marks the third time in as many years that research from the KU Kidney Institute has been included in the journal.
"We think this an important sign that we here at KU are leading the charge in translational research," said Yu, who came to KU Medical Center from the University of Southern California in 2011 to lead the Kidney Institute.
Not many people know it, but the kidneys are one of the body's leading consumers of oxygen. In fact, only the brain uses more oxygen per gram of tissue than the kidneys, so it's important to keep them running efficiently. Because kidneys are such energy hogs, it makes them susceptible to a serious condition called ischemia, which is a lack of oxygen that can cause death.
In humans and other animals, sheets of cells known as epithelia separate many parts of the body. For example, skin is an epithelium. Tiny tubes within the kidneys, known as tubules, are also epithelium. These sheets of cells act as barriers, but they also transport materials in an attempt to regulate the makeup of an organ.
The gaps between epithelial cells are sealed by tight junctions. And contrary to what their name might imply, tight junctions are actually leaky. They allow materials to get through in a process known as paracellular transport. Claudins, meanwhile, are proteins that form channels for paracellular transportation to take place.
So why are there leaks between epithelial cells at all? That was the first question Yu's team set out to answer. More specifically, why do they exist in the kidneys?
Kidneys filter blood in the body, allowing certain substances, including sodium (salt), to pass through. Much of the sodium is later reclaimed or reabsorbed in the kidney tubule by the protein claudin 2 via paracellular transport.
Salt is essential in keeping the kidneys hydrated, which is key to their health, so reclaiming the sodium would seem to be a necessity.
To test this hypothesis, Yu asked Lei Pei, a doctoral student in physiology from China who works in his lab, to investigate whether mice who had claudin 2 genetically removed had a salt-wasting trait - or were not retaining enough sodium. The thought was that if the mice lost a lot of salt in their kidneys, perhaps they would become dehydrated and possibly die.
So Yu's team, which included associate professor Timothy Fields, M.D., Ph.D., removed the claudin 2 from the proximal tubules of the kidneys in the test mice to see what would happen. But the mice did not die.
So the takeaway from all this is that it appears claudin 2, the proximal tubule and paracellular transport are not essential for the regulation of salt in the kidney, Yu said.
The big find
So if salt-wasting wasn't the answer, then what?
As with much good science, one failed hypothesis led to another discovery. Pei's test results pointed researchers to something else of importance. What they discovered was that when claudin 2 was absent, the kidneys could still transport salt, but it took a lot more energy and consumed much more oxygen.
"In essence, paracellular transport is like an energy-efficiency mechanism, and when you don't have it, your organs consume too much oxygen," Yu said. "Oxygen is needed to generate energy within cells."
So Yu's team tested whether mice with claudin 2 removed would develop ischemic injury to their kidneys. The short answer is yes. What they found was that the kidneys of the test mice were much more susceptible than the kidneys of normal mice.
This confirmed to the researchers that paracellular transport - although not an absolute must for kidneys to survive - does play a role in making kidney function more energy efficient. It also helps regulate the organ's function, so it won't use more energy than necessary and risk ischemia.
A new theory
Going forward, the team is now considering whether a kidney, which should under normal conditions be able to protect itself after sustaining an injury, might not be able to if an individual has a defect in paracellular transport in the kidney. This problem could lead to even greater injury.
Yu said it is unclear at this point whether there are naturally occurring variations in the activity of the paracellular transport pathways in humans, and whether some people might have defects that make them more susceptible to injuries to their kidneys.
In a broader context, Yu said, these recently published research findings will be of particular interest among the epithelial biology community because it asks why things have evolved the way they have in the human body? He further speculates that because tight junctions occur in almost all multi-cellular organisms, they must somehow be crucial to the very existence of the organism. But exactly how is still up for debate.
That might be a question for Yu's next research journal article.