Damage Control

One of the most devastating side effects of diabetes is kidney failure, and one of the earliest signs of damage to the kidney is disruption of its filtering capacity.

Diabetes patients who develop kidney failure must go on dialysis, seriously limiting their quality of life and significantly increasing their risk of death. The incidence of kidney disease is increasing along with rates of obesity-associated type 2 diabetes, but during the past 50 years little progress has been made toward protecting the kidney’s filter barrier.

Now Massachusetts General Hospital researchers have identified a molecule that plays a key role in the breakdown of the kidney filter, presenting a potential therapeutic target for stopping the damage before it becomes irreversible. Their report appears in The Journal of Clinical Investigation.

“Our study shows that blocking the ion channel TRPC5 may be a new treatment for diseases in which the kidney’s filter barrier is damaged,” said Anna Greka, HMS assistant professor of medicine at Mass General and leader of the study. “One in three Americans is at risk for developing chronic kidney disease from obesity, diabetes or high blood pressure. Kidney failure has been described as an emergent pandemic of our time.”

An ion channel is a pore in the cell membrane that transmits metabolic signals by allowing charged molecules, or ions—in this case, calcium—to pass into or out of cells. Disrupted calcium signaling was suggested several decades ago as a possible early event in damage to cells called podocytes that make up the kidney’s filter barrier, but the particular calcium channel that was involved had never been identified.

Some families with a rare, inherited form of kidney disease were known to have mutations in a related calcium channel called TRPC6, which led Greka’s team to investigate its role in kidney filtration. They were surprised to find that TRPC5 channels were also present in podocytes and that their activity was more damaging to the kidney filter, even in the absence of any mutations.

In a series of experiments, Greka’s team first confirmed the presence of TRPC5 channels in rodent podocytes. Then they showed that animals lacking TRPC5 did not experience the type of kidney damage typically caused by a bacterial toxin or by a chemical known to damage podocytes.

More-detailed studies revealed that those damaging agents caused TRPC5 channels to open in podocytes, admitting excess calcium and causing the cells’ cytoskeletons—their internal structural support systems—to collapse, breaking down the filters formed by podocytes.

The researchers went on to show that a recently identified TRPC5 inhibitor called ML204, discovered in the lab of study co-author Craig Lindsley of Vanderbilt University Medical Center, blocked the inrush of calcium into podocytes, preventing cytoskeletal breakdown and damage to the kidney’s filtering function. This protective effect was seen in living mice as well as in cells and tissues.

“Future work needs to focus on optimizing ML204 and other potential TRPC5 blockers to be more potent. But generally our intention is to fervently pursue TRPC5 inhibition as a possible new treatment for the kidney diseases affecting hundreds of millions of people worldwide,” Greka said.

Support for the study includes National Institutes of Health grants P30DK057521, DK083511 and DK093746 and an American Society of Nephrology Career Development grant.

By SUE McGREEVEY

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About Harvard Medical School (HMS)

Driving Change. Building Momentum. Making History.

“Since 1872, Harvard Medical School has been the incubator of bold ideas—a place where extraordinary people advance education, science and health care with unrelenting passion.

Whether training tomorrow’s doctors and scientists, decoding the fundamental nature of life, advancing patient care or improving health delivery systems around the world, we are never at rest. Allied with some of the world’s best hospitals, research institutes and a University synonymous with excellence, the School’s mission remains as ambitious as it is honorable: to alleviate human suffering caused by disease.”

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About Harvard School of Public Health (HSPH)

Harvard School of Public Health is dedicated to advancing the public’s health through learning, discovery and communication. More than 400 faculty members are engaged in teaching and training the 1,000-plus student body in a broad spectrum of disciplines crucial to the health and well being of individuals and populations around the world. Programs and projects range from the molecular biology of AIDS vaccines to the epidemiology of cancer; from risk analysis to violence prevention; from maternal and children’s health to quality of care measurement; from health care management to international health and human rights.

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About Harvard University.

Established in 1636, Harvard is the oldest institution of higher education in the United States. The University, which is based in Cambridge and Boston, Massachusetts, has an enrollment of over 20,000 degree candidates, including undergraduate, graduate, and professional students. Harvard has more than 360,000 alumni around the world.

Harvard University is devoted to excellence in teaching, learning, and research, and to developing leaders in many disciplines who make a difference globally. Harvard faculty are engaged with teaching and research to push the boundaries of human knowledge. For students who are excited to investigate the biggest issues of the 21st century, Harvard offers an unparalleled student experience and a generous financial aid program, with over $160 million awarded to more than 60% of our undergraduate students. The University has twelve degree-granting Schools in addition to the Radcliffe Institute for Advanced Study, offering a truly global education.

‘Universities nurture the hopes of the world: in solving challenges that cross borders; in unlocking and harnessing new knowledge; in building cultural and political understanding; and in modeling environments that promote dialogue and debate… The ideal and breadth of liberal education that embraces the humanities and arts as well as the social and natural sciences is at the core of Harvard’s philosophy. ’/ Drew Gilpin Faust

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* The above story is adapted from materials provided by Harvard University

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