Key points:
- Researchers determined that SOX9 activity in kidneys acts as a sensor that switches on when injured cells want to regenerate and off when they are successfully healed.
- The team found that kidney cells that are unable to regenerate recruited proteins called Wnts, and their accumulation triggers scarring called fibrosis.
- Analyzed patient data reflected a similar pattern such that patients with sustained SOX9 activation had lower kidney function, more scarring, Wnt enrichment, and increased fibrosis compared with those lacking activation.
A new study, published in Science, reveals why some injured kidneys heal while others develop scarring that can result in kidney failure. This discovery can influence the development of noninvasive tests to detect kidney scarring and therapies to reverse the condition.
Previous work demonstrated that when kidneys are injured, the surviving cells reactivate the SOX9 protein during the healing process. Building on this knowledge of the role of SOX9, the research team examined kidney damage in mice by labeling individual cells at the injury site and following the cells’ progeny over time.
When tracking the cells’ descendants, researchers found that the cells that had healed switched off SOX9 expression, while those that had not maintained SOX9 activity.
“The key to this discovery was our ability to directly compare injured kidney cells that successfully regenerated with those that did not,” explained senior author Sanjeev Kumar of Cedars-Sinai Medical Center. “SOX9 activity is 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.”
Researchers also found that kidney cells that were unable to regenerate recruited proteins called Wnts—a key player in organ development. Over time, the accumulation of Wnts triggered scarring. Conversely, deactivating SOX9 a week after injury supported kidney recovery. Collaborators observed the same recovery process in patient databases from Switzerland and Belgium. Patients with sustained SOX9 activation had lower kidney function, more scarring, Wnt enrichment, and increased fibrosis compared to those lacking activation.
Importantly, the results from the mouse model and patient databases can guide the development of new treatment options.
“These findings help us understand for the first time how the kidney’s response to injury sometimes leads to fibrosis,” said co-author Clive Svendsen of Cedars Sinai. “Future work along these lines could also advance our understanding of fibrosis in the heart, lungs, and liver.”