Reprogramming the body's energy pathway promotes self-repair of the kidneys

A team of researchers led by Dr. Jonathan Stamler, of the Cleveland School of Medicine and Cleveland University Hospital of Case Western Reserve School of Medicine, has discovered a way to improve kidney self-repair efforts. wounded. This discovery could pave the way for new drugs to stop or even reverse the progression of severe kidney failure in humans – and other life-threatening conditions of the heart, liver, and brain.

The kidneys filter waste and excess fluid from the blood, excreting the dangerous molecules in the urine. When the kidneys are damaged or failing, the waste builds up and can lead to death.

The newly discovered pathway involves reprogramming the body's metabolism to preserve the damaged kidneys. Normally, a process called glycolysis converts the glucose in food into energy, which is necessary for life to continue. But the new discovery shows that when the tissue is injured, the body can go from the repair process to the damaged cells.

Until now, the mechanisms by which the body switches between energy production (for maximum performance) and repair (in case of injury) were poorly understood. In addition, the body rarely maximizes the repair potential, generally favoring the production of energy.

In the new results published online today and in the November 29 issue of Nature, the scientific team discovered how to intensify the switching process, resulting in a cascade of tissue repair molecules that halted the progression of kidney disease in mice.

"When it is injured, the body slows the use of sugar to produce energy and uses it to repair it," Stamler said. "We show that we can control and amplify this process by moving glucose away from energy production to pathways that protect and repair cells." By accelerating and pushing the body's self-healing, we are improving the lifespan of wounded animals, we can think of it as a plan for new lines of future treatment against injured and damaged tissue. "

Normally, when cells break down lipids, sugars and proteins into glucose, the three substances are converted into intermediates that enter the mitochondria, the central cell, providing the fuel for life. The Stamler team reports that things happen very differently in the injured tissues: in the kidneys, for example, the body triggers a "Plan B" that converts glucose into new molecules that perform cellular repair.

Stamler and his colleagues discovered that a protein called PKM2 controls whether fuel (glucose) is used to power the cell or go into repair mode. The deactivation of PKM2 resulted in a significant increase in cell repair and a concomitant decrease in energy production. "After an injury or illness, the body is attempting to deactivate the PKM2 protein in order to deflect glucose into recovery mode, and as part of our research, we have increased its inhibition. kidney damage in mice. "

A key molecule in the process is nitric oxide (NO). It was already known that NO protected the kidneys and other tissues. NO is the active ingredient of nitroglycerin used to treat heart disease; it was therefore assumed that NO acted by dilating the blood vessels. But the research team discovered that NO was linked to a critical molecule called Co-enzyme A – known as the metabolite – related to glycolysis and energy production. Coenzyme A binds to and transports NO in many different proteins, including PKM2, by "quenching" them. This determines whether kidney cells use their pathways to regenerate or regenerate.

In addition to discovering that adding NO to PKM2 activates the repair, the Stamler team discovered that a protein called AKR1A1 then removes NO from PKM2, thus reactivating a robust energy generation process. Once healing is complete, this inversion effectively converts glucose into fuel. "It helps to explain why people find the ability to do exhausting activities after recovering from an injury or illness," Stamler said. When the research team turned off AKR1A1, the kidneys remained in repair mode and were highly protected against disease.

In the United States, an estimated 30 million people, or 15% of the adult population, suffer from kidney failure. Causes include medical conditions such as high blood pressure and diabetes, as well as chemotherapy and dyes used in cardiac catheterization.

Therefore, the goal is to develop drugs to inhibit PKM2 or AKR1A1. This could open new healing opportunities for millions of people around the world suffering from many conditions, injuries and illnesses, including heart disease, stroke, brain injury and kidney disease.

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Stamler is Professor of Medicine Robert and Sylvia Reitman at the Case Western Reserve School of Medicine and Chair of the Harrington Discovery Institute of the University Hospitals Cleveland Medical Center. Additional scientists from Case Western Reserve, Massachusetts General Hospital, Harvard Medical School, Massachusetts Institute of Technology, Beth Israel Deaconess Medical Center and Cedars-Sinai Medical Center also participated in the research.

This work was supported by the National Institutes of Health.

Zhou, HL et al. "Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney damage." Nature. DOI: 10.1038 / s41586-018-0749-z

For more information on the Case Western Reserve University School of Medicine, please visit: case.edu/medicine.

For more information on University Hospitals / Cleveland, Ohio, go to: UHhospitals.org.