Japanese Team Identifies Factor That Worsens Alport Syndrome in Mice

Japanese researchers have identified a factor that worsens kidney disease in Alport syndrome, just as it does in many other kidney diseases.

Scientists could use the molecular changes they identified in a mouse model of Alport to develop treatments for the rare kidney disease, according to the Kumamoto University team.

Previous studies have shown that a string of molecular events revolving around a factor called STAT3 worsens various kidney diseases. The Japanese researchers wanted to know if this was true with Alport syndrome as well.

Their report, “STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model,” appeared in the journal Nephrology Dialysis Transplantation.

The study involved mice with a mutation of the Col4a5 gene, an abnormality associated with the development of Alport syndrome in humans.

Researchers noted that the factor was more plentiful in the kidneys of Alport syndrome mice than in normal mice.

Other studies have demonstrated that activating the STAT3 pathway generates particular effects, including production of the pro-inflammatory protein IL-6. As suspected, the activation led to Alport mice having higher levels of IL-6 and other molecules.

To make sure the factor plays a role in the development of the disease, the team needed to see how the animals reacted when STAT3 was inhibited.

A compound that blocks STAT3 slowed the mice’s protein leakage in urine, compared with Alport mice who were untreated. The blocker also lowered damage to glomeruli, a kidney filtering unit whose deterioration is associated with Alport.

Researchers also discovered that blocking STAT3 suppressed gene inflammation- and fibrosis-promoting  processes. This translated to less inflammation and fibrosis, or tissue scarring, when researchers examined the mice’s kidneys under a microscope.

Their experiments showed that the treatment prevented a number of molecular changes that contribute to Alport disease processes.

RAAS inhibitors are a common treatment for Alport syndrome. But they can only delay, and not prevent, end-stage kidney disease in many patients. So the Japanese researchers said it is also crucial to address the underlying molecular changes in Alport.

Acknowledging that they studied STAT3 blockers’ effect for only a short time, they called for longer-term studies to see if the approach prevents end-stage kidney disease and prolongs survival.