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VUMC study finds molecular switch key to repair of kidney damage

Feb. 7, 2024, 9:29 AM

 

Obstructed urinary flow can cause severe injury to the collecting ducts of the kidneys. Without prompt treatment, the damage may become irreversible, requiring kidney dialysis.

Despite advances in identifying and relieving kidney obstruction, outcomes for patients have not improved significantly. Due to a lack of understanding about how the kidney repairs itself, few targeted molecular interventions have been developed to promote and accelerate repair.

Now, researchers at Vanderbilt University Medical Center have identified Rac1, a molecular switch that regulates the actin cytoskeleton of epithelial cells in the collecting ducts, as a driver of post-obstructive kidney repair.

Fabian Bock, MD, PhD

These findings “suggest that ‘mechanical’ targeting of actin cytoskeletal-based mechanisms may represent a viable therapeutic principle to enhance post-obstructive kidney regeneration,” Fabian Bock, MD, PhD, Roy Zent, MBBCh, PhD, and their colleagues report Feb. 7 in the journal Science Advances.

The collecting ducts of the kidneys play an important role in maintaining the body’s electrolyte and fluid balance as well as overall kidney health.

Bock, an assistant professor of Medicine in the Division of Nephrology and Hypertension, uses cell biology, state-of-the-art imaging, and in vitro and in vivo approaches to explore cytoskeletal remodeling in kidney development and disease.

Previously he and his colleagues have reported that Rac1 is required to maintain the integrity and function of epithelial cells, which form the protective, inner lining of the collecting ducts, and for repairing the epithelium after it has been injured by disease.

In the current study, the researchers showed, in a mouse model, that collecting ducts lacking Rac1 were unable to reconstitute or proliferate normally after the obstruction was relieved. Decreased expression of Rac1 also was observed in the malformed collecting ducts of patients with chronic kidney disease.

Other studies suggest that administration of cell permeable Rac1 peptides in another tissue — the lungs — may protect the epithelium from damage caused by viral or bacterial infections by stabilizing the actin cytoskeleton. This mechanistic approach to treatment, the researchers concluded, “is worth further exploration.”

Zent is the Thomas F. Frist Sr. Professor of Medicine.

Other VUMC co-authors were Xinyu Dong, Shensen Li, Olga Viquez, PhD, Eric Sha, Matthew Tantengco, Elizabeth Hennen, Erin Plosa, MD, Kyle Brown, PhD, Young Mi Whang, PhD, Andrew Terker, MD, Juan Pablo Arroyo, MD, PhD, David Harrison, MD, Agnes Fogo, MD, and Ambra Pozzi, PhD.

The study was supported in part by National Institutes of Health grants K08 DK134879, DK069921, DK088327, DK127589, R01 HL163195, K08 DK135931, DP5OD033412, R01 DK119212, P30 DK114809, and R01 DK056942, the U.S. Department of Veterans Affairs, and the American Society of Nephrology.

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