Innate post-AKI repair process insufficient for full recovery

Acute injuries of the kidney, which cause temporary loss of kidney function, were believed to be harmless and the kidneys could make a full recovery following these episodes. However, more research revealed that any insult to the kidneys sets up a slow loss of functional nephrons and progressive formation of fibrotic scars.

Massimo Attanasio, MD, associate professor in Nephrology, published research in JCI Insight that provides an explanation for the damaging effects of acute kidney injuries. His laboratory found that kidney tubular cells enter cellular senescence shortly after injury, slowly inducing progressive inflammation and fibrosis. Interestingly, the research reveals that by shutting down the signaling downstream of the Toll-like receptors to the NF-kB pathway of the tubular cells before cellular senescence occurs inflammation and scarring are reduced and the health of the functional tubules increases.

“This is an important discovery because it tells that specific receptors that have been extensively studied in cells of the immune system but not in epithelial cells, are the main effectors of the onset of tubular cell senescence after kidney injury,” Attanasio said. “Pharmacological targeting of these receptors before senescence has occurred may help to reduce the progressive loss of functional nephrons.”

For many years, Attanasio’s lab has been studying mouse models of the Glis2 gene, which when mutated in humans causes a very rare disease characterized by cystic degeneration and progressive kidney disease and fibrosis.

In knockout mice, the loss of Glis2 triggers the activation of the DNA damage repair response and activates NF-kb in kidney tubular cells, eventually causing cellular senescence and therefore progressive loss of kidney function and fibrosis.

“The similarity between this disease and what happens in kidneys after injury made us suspect that common pathogenic mechanisms could be shared between these two conditions. Which turned out to be the case,” Attanasio said.

Attanasio hopes to expand research in this area but is pleased by their progress. “Seeing the project go from the very early conceptual phase, through multiple experimental confirmations, and outlining a final comprehensive picture of a biological process is thrilling,” Attanasio said. “After years of hard work from all the collaborators in my laboratory, to whom I cannot be thankful enough, this brings a nice sense of accomplishment.”

Collaborating researchers on this project include pathologists Drs. Prerna Rastogi and Dao-Fu Dai, pediatric nephrologist Dr. Diana Zepeda-Orozco, and Attanasio Lab members Dr. Heng Jin, Yan Zhang, Qiong Ding, Chao Cao, Dingxiao Liu, Angela Wang, and Madison Purvis. Researchers in Tianjin and Shanghai, China, as well as at University of Texas Southwestern Medical Center and the Buck Institute for Research on Aging in Novato, California, also contributed.

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