A brand new way to understand kidney repair
Recovering from acute kidney damage isn't just about growing kidney cells-it also requires kidney tissue to stiffen temporarily, University of Connecticut researchers report Dec. 3 in the Journal of the American Society of Nephrology.
Like most of our organs, kidneys have a lot of squish. But all that squish needs a structural framework to shape it. That framework, called the extracellular matrix, or ECM, is found all over the body. That ubiquity is probably why it is often overlooked, particularly in studies of acute injury.
"When a kidney is suddenly damaged, it's mostly tubule cells. Yet very few people pay attention to the ECM at this stage," says Dong Zhou, a nephrologist at the UConn School of Medicine. The tubule cells filter the wastes from the bloodstream. If the kidney is injured, it's generally the tubule cells that need to regrow. Zhou, with postdoc (and now instructor) Yuan Gui and other team members, found out that it's the ECM that tells the tubules where and how to do it.
The body doesn't have a construction foreman to give directions on how to rebuild. Instead it uses environmental cues. The researchers noticed that the ECM tends to stiffen slightly in the injured area, and this seems to attract both cells that become tubules and cells that make more ECM. After the injury heals, the ECM relaxes. With the environmental cue (stiffness) gone, cell activity returns to normal. This is a brand new way to understand kidney repair.
Zhou's team then analyzed the ECMs of kidneys both before and after acute injuries, mapping out all the different proteins they found. They noticed the protein Mfap2 appeared early and was particularly abundant in injured ECMs, so they looked at what happened when a group of mice who lacked Mfap2 suffered acute kidney injuries. Unsurprisingly, those mice recovered much slower than normal mice.
The researchers are currently collaborating with bioengineers to develop decellularized kidney matrix scaffolds to support therapies for acute kidney injury. Interestingly, the ECM acts as a double-edged sword: while transient remodeling supports repair, excessive ECM accumulation is a well-known culprit in kidney fibrosis and uremia. Zhou's team has another paper coming soon in Nature Metabolism that systemically reveals how early-activated ECM proteins remotely regulate kidney tubule metabolism during scar tissue formation-the common endpoint of most kidney diseases.
