Local man helps unravel enigma of kidney diseaseJames Coburn
The Edmond Sun
EDMOND Thu, May 15 2008
— The mystery of a common form of kidney disease appears less elusive because of the efforts of an Edmond biomedical research scientist and his investigative team at the University of Oklahoma Health Sciences Center.
Associate professor of cell biology Leo Tsiokas, Ph.D, focuses his research on polycystic kidney disease (PKD). And in September, Tsiokas’ paper “PKD2 Functions as an Epidermal Growth Factor-Activated Plasma Membrane Channel” was published in two internationally recognized biomedical journals, Molecular Cellular Biology and Science.
“The kidney is actually supposed to be small like a fist,” said Tsiokas in describing PKD. “It actually become huge. So it’s full of cysts, full of fluid.”
Renal failure occurs when the cysts damage functional parts of the kidney. PKD is a systemic disease impacting the liver and most patients die due to cerebral aneurysms. Fertility problems can occur.
Genetic factors cause two forms of the PKD — dominant and recessive.
Dominant PKD means a parent with the disease has a 50 percent chance of genetically passing the disease to their child. One in 1,000 people in the United States has the dominant form, Tsiokas said, making it one of the more common genetic diseases.
Recessive PKD occurs in one out of 10,000 people in the United States and occurs when children inherit the disease from both parents. Most children with recessive PKD die before they are 12 years old, he added.
Scientific studies already had located the defective PKD genes before Tsiokas’ investigation. Tsiokas’ basic research is the first to show how one of the gene mutations results in PKD. Two distinct mutated genes, PKD1 and PKD2, cause the dominant form. Tsiokas’ research concentrates on PKD2.
“There was evidence that the protein might work as a channel,” Tsiokas said. “What channels do — there are proteins that form pores in the plasma membrane. And they allow ions to go in and out. The cell absolutely requires ions to function.”
An ion channel is a protein that stimulates the body’s electrical system in membranes.
Closed channels need to be activated to let calcium, magnesium, potassium and sodium enter.
Once opened, millions of ions come in to benefit the cells before the channel closes after receiving the appropriate amount of ingredients.
“We found this growth factor acts through its signal, acts through its receptor,” he said.
As a soluble molecule, it binds to the channel’s protein receptor placed outside the cell.
“We worked out the molecular mechanism,” Tsiokas said. “We identified how this pathway works.”
A group of organic compounds, a lipid, was found to bind the channel, keeping it closed. Enzymes are activated when the growth factor binds to its center, making the channel open. But the channel remains closed in PKD patients with mutations that cannot respond to growth factor stimulation.
“This would suggest that this pathway is physiologically important and this may explain why these patients have the disease,” Tsiokas said.
He said there is the possibility that other growth factors of the body also can open the channel.
“Or in any situation if you have a build up of these lipids, it may produce the disease because the channel can stay closed,” he said. “This is the first time I’ve said that. I should have included it in the paper.”
The mechanism of opening the channel has been defined. So further investigation will focus on how the channel interacts with about 20 proteins. A tiny electrical current is measured as ions pass through the cell.
“We need to understand anything about this molecule,” Tsiokas said. “It’s something that kills a lot of people so we need to know everything. So we’re going to try and find out every amino acid in the important part of the molecule.”
(Features Editor James Coburn may be reached via e-mail at jcoburn@edmond sun.com.)
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