Treating hypertensive rats with the broad-acting anti-inflammatory drug pentosan polysulfate preserves the kidney's ability to regulate pressure placed on tiny filters called glomeruli, they report in the May issue of American Journal of Physiology – Renal Physiology. A million of these fragile structures are responsible for filtering the body's total plasma volume 60 times daily.
Therapeutic intervention is a long-term goal, said Dr. Edward W. Inscho, corresponding author and physiologist in the MCG Schools of Graduate Studies and Medicine "Because the job is big, the kidneys are vulnerable to injury. If we can keep them functioning longer, quality of life is going to be better longer."
But he notes that this exact approach isn't a treatment option primarily because of side effects that can result from long-term use of anti-inflammatory drugs.
Hypertension and diabetes take a similar toll on kidneys and together, the pervasive conditions are creating a rapidly growing number of patients in kidney failure. "The number of people going to dialysis because of these two maladies just grows exponentially so there is a really good reason to figure this out," said Inscho, who recently received a $1.8 million, five-year grant from the National Heart, Lung and Blood Institute to help do just that.
In a rather vicious circle, kidneys are hurt by and contribute to hypertension; which comes first remains unresolved. But one key way hypertension hurts kidneys is by blunting the function of afferent arterioles, tiny blood vessels that feed the filtering units.
Much like a dam operator controls water flow into a river, a mechanosensor, likely located inside the smooth muscle cells that form the blood vessel walls, keeps tabs on the pressure of the blood flowing through the afferent arteriolar into the filters. If pressure gets too high, it prompts the small vessel to contract.
"You want the vasculature to constrict because filters are very delicate and the kidneys want to keep blood flow and filtration relatively constant," said Inscho noting that this balancing act enables kidney tubules, which reabsorb good things like glucose and amino acids, to do their job.
His animal studies have shown that mechanosensor function falters after just three days of high blood pressure. "The blood vessel does not seem to recognize the blood pressure increase," Inscho said. Even slightly elevated pressures resulting from too much salt consumption can render them less responsive but, at least initially, not lost. Rather the vessel's ability to sense and respond to pressure seems inactivated: when Inscho applies a vasoconstrictor agent directly onto the afferent arteriole, for example, it contracts. In the face of regular anti-inflammatory therapy, he's finding it retains the ability to sense pressure change and respond appropriately.
Inscho's new grant will help sort through just how the kidneys autoregulate pressure in normal scenarios, such as the typical blood pressure fluctuations that occur in healthy people throughout the day.
He also wants to study the role the inflammatory factors TGF-â and MCP-1 play in arteriole dysregulation. Both factors are elevated in high blood pressure and implicated in other types of vascular injury. Preliminary evidence suggests a strong link; that the factors set up some sort of signaling event that turns mechanosensors off or at least down. Ironically, impaired autoregulation leads to increased production of the inflammatory factors.
"We have data that argue that TGF-â can definitely cause these blood vessels to fail," Inscho said. "If you apply the cytokine to a healthy kidney, the blood vessel will not respond correctly; wash it off and it does. Now we also have data that if we protect the kidneys from MCP-1, we can improve the function of these vessels."
He's looking at the impact of anti-inflammatory drugs pentosan polysulfate as well as mycophenolate mofetil because of existing evidence that their use reduces protein excretion in the urine, a sign of kidney damage. Rather than as a potential therapy, he views the drugs as tools for helping dissect a complex process.
"Hypertension-related kidney damage is multifaceted, but part of that cascade of progression to injury is functional impairment of that blood vessel. We have established that, I think, unequivocally," Inscho said.
"The grant will enable us to get more information about normal function and pathology all at the same time."
Toni Baker | EurekAlert!
'Icebreaker' protein opens genome for t cell development, Penn researchers find
21.02.2018 | University of Pennsylvania School of Medicine
Similarities found in cancer initiation in kidney, liver, stomach, pancreas
21.02.2018 | Washington University School of Medicine
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
21.02.2018 | Life Sciences
21.02.2018 | Life Sciences
21.02.2018 | Materials Sciences