New perspectives on thick ascending limb function and cell types

The thick ascending limb (TAL) of Henle's loop has long fascinated scientists and clinicians and interest has increased recently because genes expressed there are useful biomarkers for kidney injury. Although the classic TAL cell transport model suggests a single TAL cell type and has remained largely unchanged since the 1980s, new molecular tools and mathematical models suggest that canonical views should be revisited. For example, in contrast to early suggestions, experimental work and mathematical models suggest that the luminal sodium concentration declines along the entire length of the TAL and approaches but does not reach a constant limiting value in vivo. Additionally, sodium chloride transport along the TAL may not be as highly efficient as previously postulated. Finally, recent analyses that combine immunocytochemistry, transcriptomics, and functional studies suggest that the TAL comprises three distinct cell types, in addition to macula densa cells, only one of which exhibits apical potassium channels. A second cell type has basolateral but not apical potassium channels and appears poised to mediate transepithelial calcium and magnesium transport. A third cell type is only found in the inner stripe of the outer medulla and shares some properties of the other two; it may be important for sodium and potassium absorption. Combining new insights such as these with ongoing studies of kidney disease and kidney injury, such as the Kidney Precision Medicine Project, may provide new understanding of pathogenesis and treatment.