A molecular switch that regulates the cytoskeleton — the cellular equivalent of our skeleton — is required for the maintenance and integrity of the kidney collecting duct, Vanderbilt researchers have found.
The discovery, reported in the Nov. 1 issue of the Journal of Cell Biology, could aid efforts to promote kidney regeneration after injury or to develop engineered organs.
The publication adds to the growing accomplishments of first author Fabian Bock, MD, PhD, instructor in Medicine in the Division of Nephrology. Bock is a member of the Harrison Society, a group of physician-scientists who complete their internal medicine residency clinical training in two years and then spend three years doing research.
“Fabian came to Vanderbilt for this fast-track program, completed his clinical training, and in just over two years in the lab has been awarded a fellowship grant from the American Society of Nephrology and now published a highly cited paper in a top-rate journal,” said Roy Zent, MBBCh, PhD, Thomas F. Frist Sr. Professor of Medicine and Bock’s mentor. “Programs like the Harrison Society are one of Vanderbilt’s strengths. We work very hard to recruit outstanding physician-scientists like Fabian.”
Bock was drawn to the Vanderbilt program for its emphasis on basic and translational research, he said. “There are a lot of clinician-scientist training programs, but Vanderbilt’s program is geared toward people going into the lab and working at the bench. That’s pretty rare these days.”
Bock is using cell biology, state-of-the-art imaging, and in vitro and in vivo approaches to explore cytoskeletal remodeling in kidney development and disease. In the current paper, he and his colleagues focused on the protein Rac1, which previous studies had shown is an important regulator of the cytoskeleton during development, particularly for branched structures.
“We hypothesized that if we took Rac1 out of the collecting system of the kidney, which develops via branching morphogenesis, that kidneys wouldn’t form properly,” Bock said. “But unexpectedly, they did form, and there wasn’t a major developmental defect in these mice.”
Instead, the investigators discovered a key role for Rac1 as the mice aged: it was required to maintain the integrity and function of epithelial cells in the collecting duct. The team defined the molecular mechanisms by which Rac1 regulates the cytoskeleton and maintains the polarity (the differing apical and basolateral surfaces) of epithelial cells.
“For proper organ function, whatever the organ is, cells must have structure,” Zent said. “Rac1 is a critical molecular switch that controls how the cytoskeleton is put together and regulated.”
Understanding the molecular mechanisms controlling the cytoskeleton and cell structure is important for growing engineered organs and promoting tissue regeneration after injury, Bock said.
“How does this nicely formed epithelial barrier re-establish itself after it has been perturbed? The molecular mechanisms we’ve defined and the dynamic regulation of the cytoskeleton will be very important for that process.”
Bock’s clinical interests include chronic kidney disease, diabetic nephropathy and dialysis.
The research was supported in part by U.S. Department of Veterans Affairs Merit Review awards and grants from the National Institutes of Health (DK069921, DK127589, DK119212, DK108968, DK056942, DK114809, and DK007569) to Zent and co-authors Ambra Pozzi, PhD, Leslie Gewin, MD, and Agnes Fogo, MD. Bock is the recipient of an American Society of Nephrology Ben J. Lipps Research Fellowship. Co-author Andrew Terker, MD, PhD, is the recipient of an American Heart Association postdoctoral fellowship.