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Repairing Injured Kidneys Through Regeneration

Kidney

The capacity to regenerate has mythic qualities for most of us, but the human body has very little ability to regrow body parts on its own compared to say, flatworms that can regenerate a whole new self from small pieces, or some reptiles and amphibians that can regrow lost tails or limbs. In mammals, regeneration is largely relegated to wound healing, primarily in the liver and kidney.

The kidney has a tremendous capability for regeneration following injury, but how it occurs is still largely unknown, said Katalin Susztak, MD, PhD, an associate professor of Medicine. To pull back the curtain on regeneration, so to speak, her team isolated mouse kidney cells that can proliferate and have the capacity to differentiate into other types of mature cells. Gene expression profiling indicated that these cells were rich in the proteins Sox9, Lgr4, and Pax. They published their paper this week online ahead of print in Cell Reports.

Image6In regenerating kidneys, Sox9 expression rose quickly, in particular, and close to 90 percent of proliferating cells were Sox9 positive. Sox9 is a transcription factor that governs the expression of genes during kidney development. Therefore, she said, maybe it is less surprising that Sox9 also controls the transcriptional program that governs regeneration of an injured kidney. In test tube experiments, Sox9-positive cells showed unlimited proliferation and multi-lineage differentiation capacity.

Using a molecular tagging method, the team showed that Sox9-positive cells were the sources of new daughter cells and contributed to the regeneration of proximal tubule, loop of Henle, and distal tubule segments of the kidney, but not to the collecting duct and glomerular epithelial cells. These last two kidney cell types develop from a cell line going back to embryo development compared to the first three kidney cell types.

The team found that after injury (experimentally caused by a toxic chemical) close to 80 percent of new kidney cells that regenerated originated from the Sox9-positive population of cells. Genetic deletion of Sox9 severely impaired the regeneration of the kidney after injury and resulted in scarring of the kidney. These studies indicate that Sox9 is not only a marker of these cells, but also directs aspects of regeneration.

“Overall, we showed that Sox9-positive cells have progenitor-like properties in cell culture experiments, proliferate extensively, and contribute to epithelial regeneration following injury in a real kidney,” Susztak said. “Perhaps this information will be useful to learn how to one day generate kidney cells at will. This is an important endeavor as thousands of patients die daily because of kidney injury from systemic disease and other causes.”

Image:Double immunostaining of Sox9 (red) with LTL (a marker of proximal tubule; green), PNA (marker of loop of Henle/distal tubule), or DBA (a marker of collecting duct).

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