New heart-kidney molecular signal identified

Michael Hutchens and Mahaba Eiwaz

An OHSU-Pacific Northwest National Laboratory collaboration is key to a new identification of molecular signals specific to heart injury.

Cardiovascular disease is one of the most common reasons people land in the hospital, and these admissions are very often complicated by acute cardiorenal syndrome. ACS affects up to 30 percent of people with severe heart disease; the kidneys don’t receive enough blood supply. ACS can also lead to chronic kidney disease and the need for dialysis or transplant.

Even though advanced therapies such as left ventricular assist devices and extracorporeal membrane oxygenation rapidly restore critical blood flow to the kidneys, ACS can still occur, according to investigator Michael Hutchens, M.D., M.A. “And the incidence is rising.”

Quest to understand molecular signals

Previous studies suggest that hormonal signaling between the heart and kidney during acute cardiac illness might influence kidney function, but those connections weren’t fully understood. New research by a team led by Hutchens sheds new light on those connections. The paper, “Glomerular filtrate proteins in acute cardiorenal syndrome,” published in JCI Insights on Feb. 26, 2019.

“Identifying the molecular signals specific to heart injury and received in the kidney could lead to novel therapy or prevention for ACS, and get people out of the hospital sooner,” said Hutchens, critical care physician, VA Portland Health Care System, and associate professor of anesthesiology and perioperative medicine, OHSU School of Medicine. Pictured above are Michael Hutchens and co-author Mahaba Eiwaz in the Hutchens lab.

The research team decided to tackle this question, looking for new “cardiorenal connectors” by investigating the proteins that pass through the kidney’s filter to reach its cells.

Urine is not the whole story

A major challenge in studying these types of proteins is that the kidney adds and subtracts proteins from the filtrate, which is water and molecules that result from the kidney’s filtration process before it excretes urine. That means urine doesn’t tell the whole story, said Hutchens, and “can contain some untruths.”

Prior investigators retrieved filtrate from within the kidney before the adding and subtracting step, but were only able to collect unmeasurably small quantities. These are so small that it’s been impossible to characterize all the proteins in the retrieved fluid. Additionally, using a mouse model makes this difficult, because not all mice have accessible filtrate.

The answer: Multiphoton 3D microscopy

To overcome these challenges, the team turned to Paul Piehowski, Ph.D., a proteomics chemist at Pacific Northwest National Laboratory, who develops techniques for protein analysis in nano-sized samples, a field called nanoproteomics.

A formal research collaboration between OHSU and PNNL, called the Precision Medicine Innovation Co-Laboratory, or PMedIC, helps scientists from both organizations improve human health by focusing research on highly complex sets of biomedical data and the tools to interpret them. The scientists utilize integrated ‘omics, data science and imaging technologies in their research in order to advance precision medicine.

Hutchens and Piehowski devised a new method that could retrieve kidney filtrate in all mice using multiphoton 3D microscopy. In the mouse model experiment, subjects experienced cardiac arrest and received cardiopulmonary resuscitation, performed just as it is in humans. Using the new imaging technique, researchers retrieved and analyzed the mouse filtrate. They compared those results against the results of control subjects exposed to a sham procedure.

Novel heart protein found

The team found that, compared with filtered proteins from other organs, proteins from the heart increased substantially in the filtrate after CA/CPR. They confirmed their results using mice in which the ability to change the proteins in urine is impaired, and found the same result — CA/CPR greatly increases the heart proteins that filter in the kidney.

“As a neuroscientist who spends her time thinking about circuits and connections, I was intrigued to learn about this molecular ‘connection’ between the heart and kidney,” said Mary Heinricher, Ph.D., associate dean for research, OHSU School of Medicine. “This is one example of the exciting science that becomes possible as our own collaboration and connection with PNNL grows.”

“Some of these heart proteins have been suspected or known to reach the kidney, however, we found a novel heart protein — cardiac LIM — in the kidney filtrate, previously unknown to ever be present in the kidney,” said Hutchens. “Because this protein plays a role in heart fibrosis in some settings, we thought it might be related to chronic fibrotic changes in the kidney — part of chronic kidney disease.”

The researchers injected recombinant cardiac LIM protein into normal mice, which developed kidney dysfunction, kidney fibrosis, and other signs of chronic kidney disease.

“This is the first time a heart protein has been identified playing such a role in kidney biology and suggests there may be other such signals, from the heart, and perhaps other organs,” said Hutchens.

Next steps

Paper of the month The School of Medicine’s Paper of the Month for February 2019 is “Glomerular filtrate proteins in acute cardiorenal syndrome” published in JCI Insight.

The Hutchens Lab is now investigating new questions about the cardiac LIM protein, such as how and whether it does what scientists have observed.

If clinicians know what signals are being sent at the time of hospital admission for acute cardiovascular disease, such as cardiac arrest or myocardial infarction, it might become possible to interrupt the signals and stop the later development of kidney disease.

Citation

Glomerular filtrate proteins in acute cardiorenal syndrome; Rumie Wakasaki, Katsuyuki Matsushita, Kirsti Golgotiu, Sharon Anderson, Mahaba B. Eiwaz, Daniel J. Orton, Sang Jun Han, H. Thomas Lee, Richard D. Smith, Karin D. Rodland, Paul D. Piehowski, Michael P. Hutchens; Published February 21, 2019, JCI Insight. 2019;4(4):e122130

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