Researchers discover enzymes kidneys use to protect themselves from inflammation

Inflamed kidney cells produce one of the same inflammation-suppressing enzymes fetuses use to survive, according to a study published in the Journal of Immunology.

In an animal model of inflammatory kidney disease, researchers from the Department of Medicine at the Medical College of Georgia at Georgia Regents University (MCG) found kidney cells respond to potentially destructive inflammation by producing the enzyme indoleamine 2,3-dioxygenase(IDO).

IDO sets in motion a chain of events that can eliminate the damaged protein produced during inflammation, allowing cells to better recover, said Dr. Tracy L. McGaha, immunologist in the Department of Medicine at MCG and corresponding author of the study. They also found evidence of the same protective scenario in kidney tissue from humans with a variety of inflammation-related conditions.

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Researchers blocked IDO in an animal model, and then gave a fatal dose of an antibody to collagen found in the kidney, which accelerated the process whereby the normal structure of the kidney is replaced with dysfunctional scar tissue.

"What we are realizing is that most diseases have common pathways to either inflammation, fibrosis, or recovery," said Michael P. Madaio, nephrologist and MCG Medicine Department Chairman.

"When the kidney cells couldn't make IDO, the inflammation that was induced by the antibody caused those kidney cells to die," McGaha said.

Even when they gave only enough antibody to induce mild inflammation in mice lacking IDO, it resulted in rapidly progressive and deadly kidney destruction. "If you inhibit the mechanism, the disease is worse," McGaha said.

The role of podocytes

Once they saw IDO's natural protective role in the kidney, the researchers found it was coming from the podocytes, a type of kidney cell with appendages that wrap around the capillaries of the filtering units, enabling the kidney to recirculate needed substances, such as sodium and protein, and excrete toxins in the urine that can cause damage. In humans and animal models, loss of podocytes, which have a limited ability to replicate, is directly linked to the kidneys' lost ability to filter.

According to the researchers, podocytes make IDO, which consumes tryptophan, an amino acid that is essential for metabolism. Another enzyme, GCN2, is activated by the dearth of amino acids, initiating a stress response in the kidney cells, which induces a natural cell process called autophagy.

While part of what autophagy does is enable the cell to consume itself, the goal is to enable the cell to survive and/or replicate. Autophagy slows production of the damaged protein made by the inflamed cells and eats up the damaged protein already made, McGaha said. If it's early enough in the process, autophagy essentially clears out the damage, and the kidney cells recover. If autophagy goes on too long, because inflammation goes on too long, it triggers another natural cell process, called apoptosis, or cell suicide. It was already known that disrupting autophagy in mice leads to chronic, progressive kidney disease.

The researchers found that activation of the IDO-GCN2 pathway was essential to ensuring autophagy.

"The process of autophagy didn't happen in the podocytes without those two," McGaha said. "The podocytes went ahead and died."

Potential treatment target

When the researchers looked at kidney tissue from humans with a wide range of kidney disease, they also found levels of IDO and stress genes were way above baseline for healthy individuals,said Dr. Michael P. Madaio, nephrologist and MCG Medicine Department Chairman, further indicating that the IDO-GCN2 pathway is functional in many types of kidney disease and identifying it as a potential new treatment target.

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When they gave DNA nanoparticles known to induce IDO, they found healthy mice kidneys produced IDO. When they gave mice a lethal dose of the collagen-injuring antibodies and the DNA nanoparticles at the same time, the IDO-GCN2 pathway was protective. The researchers also directly activated GCN2, and that worked as well, reinforcing the theory that it takes the enzyme pair to provide protection.

"What we are realizing is that most diseases have common pathways to either inflammation, fibrosis, or recovery," said Madaio, a study coauthor. "What Dr. McGaha is doing is discovering those pathways or identifying new pathways in inflammation and protection."

Next steps include learning more about how autophagy protects podocytes. Researchers also want to confirm their observation that activation of the IDO-GCN2 pathway is common in kidney inflammation. -by Rebecca Zumoff