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Unraveling the molecular nature of blood vessel specialization in the kidney

Scientists have identified critical sets of genes turned on in individual cells within discrete, specialized zones of blood vessels in the mouse kidney during development and adulthood—findings that could have important implications for developing artificial kidney technologies. The activities of nephrons— the essential structural and functional units of the kidney—would be impossible without the blood vessels that intertwine with them. These blood vessels, or vasculature, are not uniform, but instead become specialized according to their position within a nephron to help carry out the precise function of each nephron segment or substructure (e.g., retention of sugars, reabsorption of water to help maintain fluid balance in the body). This vascular specialization by zone is essential for proper kidney formation and function, but the molecular pathways driving this specialization have been unknown, hindering the development of promising technologies such as artificial kidneys. A research team recently identified critical molecules regulating this process in mice.

Using sophisticated cell-sorting techniques, the scientists isolated individual blood vessel cells, called endothelial cells (ECs), from the kidneys of developing mouse embryos, as well as from postnatal and adult male mice, and identified all the genes that were turned on in those individual cells. They also compared the genes turned on in ECs in bulk from kidneys to those of the lung, liver, and heart, to identify those with activity specific to kidneys. Comparisons of the kidney-specific EC gene “molecular profiles” revealed several distinct clusters of genes that correspond to the different structures and functional regions within the nephron; there were also significant differences between mouse embryonic and adult kidneys. Further examining ECs, the scientists found that different genes were active in different vascular zones, such as genes involved in regulating the absorption of specific molecules, providing developmental instructions to neighboring cells, or turning other critical genes on or off. The researchers then tested the importance of the gene Tbx3, which they had found to be particularly active in a critical segment of the nephron called the glomerulus. They genetically deleted Tbx3 specifically in glomerulus ECs in male mice and found defects in the structure of the glomerulus that affected blood pressure and led to aberrant filtration of molecules from the blood. With other experiments, these results indicate that Tbx3 governs genes important to glomerular blood vessel development and function. Importantly, the scientists also tested the gene in cultured human endothelial cells and found that human TBX3 likely has a similar function as the mouse gene.

The distinct kidney EC molecular profiles identified in this study shed critical light on the processes that create and maintain discrete vascular zones in the nephron. These findings could provide a foundation to help accelerate the engineering of functional artificial kidneys.

Barry DM, McMillan EA, Kunar B,…Rafii S. Molecular determinants of nephron vascular specialization in the kidney. Nat Commun 10: 5705, 2019.