A Brief History of the Cortical Thick Ascending Limb: a Systems-Biology Perspective.

Here, we review key events in the accrual of knowledge about the cortical thick ascending limb (CTAL) of the kidney, starting with its initial characterization by Maurice Burg in 1973. Burg's work showed that the CTAL actively reabsorbs NaCl and that, because its water permeability is virtually zero, it can lower the luminal NaCl concentration to a 'static head' level well below blood levels. This process is central to the kidney's ability to excrete a dilute urine in states of high water intake. Following Burg's original observations, Greger and Schlatter, working in the 1980's, identified the membrane transport processes responsible for transepithelial NaCl transport in the CTAL. In the 1990's, several investigators identified the key transporter genes and proteins at a molecular level by cDNA cloning. The successful completion of human and mouse genome sequencing projects at the turn of the century, led to development of transcriptomic and proteomic methodologies that allowed identification of complete transcriptomes and proteomes of CTAL cells. Knowledge accrual was enhanced by the development of differential equation-based models of transport in the CTAL in the 2010's. Here we used a simplified mathematical model of NaCl ('salt'), urea and water transport in the CTAL to address three key questions about CTAL function: 1) What is the mechanism of Burg's 'static head' phenomenon? 2) How does the kidney compensate for the very short length of the CTALs of juxtamedullary nephrons? 3) Which of the three isoforms of the apical Na-K-2Cl cotransporter (NKCC2) dominates functionally in the CTAL?