SOX9 Activity Found to Influence Kidney’s Response to Injury

Researchers at Cedars-Sinai have uncovered the mechanism behind why some injured kidneys can regenerate while others develop scarring that may progress to kidney failure. Published in Science, their study offers insights that could pave the way for noninvasive tests to detect kidney scarring and potential therapies to reverse the condition.

“The key to this discovery was our ability to directly compare injured kidney cells that successfully regenerated with those that did not,” explained Sanjeev Kumar, senior author of the study. “Injured cells activate a protein called SOX9 to regenerate themselves. When they have healed, the cells silence this protein. Cells that aren’t able to regenerate leave SOX9 active, and this leads to a type of scarring called fibrosis. But when we deactivate SOX9 in a timely fashion, the scarring literally goes away.”

The kidneys, vital for filtering waste from the blood, can sustain injuries from various factors like diabetes, high blood pressure, infections such as COVID-19, and certain medications. The study in mice revealed that cells with silenced SOX9 expression healed fully, while those with active SOX9 continued attempts at regeneration, resulting in scarring.

In the study, Kumar and fellow investigators studied kidney damage in laboratory mice. They labeled individual cells at the point of injury, then followed how the cells’ progeny evolved over time. “At Day 10, some cells’ descendants were fully healed while others were not,” Kumar said. “The cell lineage that healed had switched off SOX9 expression, while the unhealed lineage, in a continuing attempt to fully regenerate, maintained SOX9 activity. It’s like a sensor that switches on when cells want to regenerate, and off when they are restored, and we are the first to identify this.” 

By studying patient data from collaborating institutions, researchers confirmed their findings. “We could see that by Day 7, human patients with transplanted kidneys that were slow to begin working also activated SOX9,” Kumar said. “And in our collaborators’ database, we were able to distinguish that patients who had sustained SOX9 activation had lower kidney function and more scarring than those who did not. Human kidneys with cells that maintained SOX9 were also enriched with Wnts and showed increased fibrosis.”

This discovery opens avenues for drug development and noninvasive biomarkers for diagnosing kidney fibrosis without the need for risky biopsies.