MDI Bio Lab Reveals a Fundamental Driver of Kidney Disease

Press Release

MDI Bio Lab Reveals a Fundamental Driver of Kidney Disease

Zebrafish research details how a dietary molecule in the gut's microbiome affects kidney health

As the holiday season arrives, many of us know the feeling: a crowded table, a generous plate, and that after-dinner slowdown often referred to as a "turkey coma" and blamed on the amino acid tryptophan.

It's a bit of a myth: turkey is no richer in tryptophan than many everyday foods, and tryptophan itself isn't what puts us to sleep. In reality, this nutrient plays a far bigger role behind the scenes, helping organs navigate stress, manage energy, and keep inflammation in check.

Now, new research from MDI Biological Laboratory and Hannover Medical School shows that when the body's handling of tryptophan goes awry, it can leave the kidney's most delicate filtration cells vulnerable. The findings offer new insight into how chronic kidney disease may begin before symptoms appear, and how one day, it might be stopped earlier or even prevented entirely.

A small fish reveals a basic mechanism behind a massive health problem

Published in the peer-reviewed FASEB Journal, the research describes for the first time and in step-by-step detail a novel link between how the body processes tryptophan and the strength of the kidney's filtration barrier. As tryptophan is broken down, it is converted into metabolites known as kynurenines.

The new research relied on a unique line of fluorescent, transgenic zebrafish developed by MDI Bio Lab President Hermann Haller, M.D., and his colleagues. In these fish, disturbances in this metabolic pathway led to swelling, fluid buildup, and leakage of large proteins from the bloodstream into urine. These are classic hallmarks of early kidney injury and disease in humans.

Chronic kidney disease affects millions of people worldwide, yet the reason abnormal kynurenine levels show up so often in patients has remained something of a mystery. This study suggests these abnormalities may not merely be innocent metabolic byproducts, but rather active contributors that can weaken the filtration barrier and lead to kidney disease.

"Since tryptophan is mostly processed in the gut and then released into the blood stream, these novel findings highlight how disturbances in our diet and the composition of our gut flora may be linked to the development of chronic kidney disease," Haller said. "It also highlights how the zebrafish helps us understand the very basic mechanisms involved in a huge health problem and opens a door to new therapeutic strategies."

A dietary molecule with a bigger job than expected

Tryptophan is absorbed from a wide range of foods, including holiday staples such as turkey and cream, and is essential for building proteins and for producing serotonin, melatonin, and vitamin B3.

Beyond these well-known roles, most tryptophan is broken down into smaller molecules called kynurenines. Some kynurenines aid the production of NAD, a crucial enzyme required for cellular energy production, while others serve as molecular signals that regulate cell behavior.

These metabolites circulate widely in the body, and clinical studies have long associated abnormal kynurenine levels with chronic kidney disease, cardiovascular complications, and inflammation. What hasn't been clear is why these changes occur, and how they might directly weaken the kidney's filtration system.

That's where the zebrafish comes in. Its basic kidney filtration unit, the glomerulus, shares striking similarities with those in humans, particularly in the form and function of its most delicate filtering cells. Like a microscopic coffee filter, the glomerulus lets waste molecules pass while holding back larger, physiologically valuable proteins.

Using this model, MDI Bio Lab scientists suppressed and activated specific enzymes in the kynurenine pathway in zebrafish larvae, whose transparency allowed them to observe disturbances unfolding in real time. This kind of live visualization simply isn't possible in mice, whose opaque development makes the same level of observation far more challenging.

It helped that some of the fish were engineered so that targeted proteins would fluoresce if they leaked through the filtration barrier - like dye seeping through a torn filter.

The results were consistent across multiple experiments:

• Metabolite imbalance - Abnormal activity in key tryptophan-derived metabolites signaled early structural and functional stress in the kidney.
• Fluid buildup and swelling - larvae developed yolk-sac and cardiac edema.
• Protein loss from the blood stream - fluorescent blood proteins leaked through the filtration barrier, a condition known as proteinuria that underlies many kidney diseases.

Podocytes: a weak link when tryptophan metabolism goes wrong

To pinpoint which kidney cells are most vulnerable, the team used human and mouse cell cultures to examine podocytes - the highly specialized, delicate cells that form the kidney's final filtration barrier.

When kynurenine processing was disrupted, podocytes shrank and lost their normal shape, peeled away from anchoring surfaces, and struggled to maintain the small electrical charge that helps prevent proteins from slipping through the kidney's filter. They also struggled to boost energy output when the kidney needed extra work done.

Notably, all of these changes occurred before any evidence of cell death, pointing to an early phase of dysfunction that precedes irreversible loss of podocytes. Identifying this window of vulnerability points to a critical opportunity: a phase where future therapies could intervene to preserve podocyte function and potentially slow or prevent kidney disease progression.

More than a Decade's Work Among Collaborating Maine Research Institutions

Haller added that the findings cap more than a decade of collaborative work among scientists at several Maine research institutions - MDI Bio Lab, the Jackson Laboratory and MaineHealth Institute for Research.

"It took several years to delineate the function of the pathway, using a genetic screen in mice developed by JAX, in MDI Bio Lab's zebrafish, and in collaboration with MaineHealth clinical researchers, in human patients with kidney disease," Haller said. "We published that work in 2016. In the present publication we have now unraveled the precise cellular and molecular mechanisms of this disease-causing pathway."