SOX9 activity determines kidney regeneration with or without fibrosis

Investigators have discovered why some injured kidneys heal while others develop scarring that can lead to kidney failure. Their findings, detailed in a paper published in the peer-reviewed journal Science, could lead to the development of noninvasive tests to detect kidney scarring and, eventually, new 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,” said the 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, two fist-sized organs that filter waste from the blood, can be injured by diabetes and high blood pressure, serious infections such as COVID-19, and overuse of antibiotics and non-steroidal anti-inflammatory pain medications, said the author. 

The SOX9 protein plays a major role in organ development but is not active in healthy adult kidneys. In previous work at another institution, the team found that when kidneys are injured, the surviving cells reactivate SOX9 as part of the healing process.

In this study, the 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,” said the author. “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.” 

Further, investigators discovered that cells that were unable to regenerate began recruiting proteins called Wnts, another key player in organ development. Over time, this accumulation of Wnts triggered scarring. And they found that deactivating SOX9 a week after injury promoted kidney recovery.

“We could see that by Day 7, human patients with transplanted kidneys that were slow to begin working also activated SOX9,” the author 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.”

These discoveries provide targets for drug development, as well as for noninvasive biomarker discovery permitting diagnosis of kidney fibrosis through the urine, the author said. Currently, the only available test for kidney fibrosis is a biopsy, which carries many risks.

“Elucidating the mechanisms of scarless healing versus fibrosis has eluded investigators for decades and has implications beyond the kidney, including for certain cancers,” said a co-author of the study.

“These findings help us understand for the first time how the kidney’s response to injury sometimes leads to fibrosis,” co-author said. “Future work along these lines could also advance our understanding of fibrosis in the heart, lungs and liver.”