Axial and cellular heterogeneity in electrolyte transport pathways along the thick ascending limb

The thick ascending limb (TAL) extends from the border of the inner medulla to the renal cortex, thus ascending through regions with wide differences in tissue solute and electrolyte concentrations. Structural and functional differences between TAL cells in the medulla (mTAL) and the cortex (cTAL) would therefore be useful to adapt TAL transport function to a changing external fluid composition. While mechanisms common to all TAL cells play a central role in the reclamation of about 25% of the NaCl filtered by the kidney, morphological features, Na⁺ / K⁺ -ATPase activity, NKCC2 splicing and phosphorylation do vary between segments and cells. The TAL contributes to K⁺ homeostasis and TAL cells with high or low basolateral K⁺ conductances have been identified which may be involved in K⁺ reabsorption and secretion respectively. Although transport rates for HCO3- do not differ between mTAL and cTAL, divergent axial and cellular expression of H⁺ transport proteins in TAL have been documented. The reabsorption of the divalent cations Ca²⁺ and Mg²⁺ is highest in cTAL and paralleled by differences in divalent cation permeability and the expression of select claudins. Morphologically, two cell types with different cell surface phenotypes have been described that still need to be linked to specific functional characteristics. The unique external environment and its change along the longitudinal axis require an axial functional heterogeneity for the TAL to optimally participate in conserving electrolyte homeostasis. Despite substantial progress in understanding TAL function, there are still considerable knowledge gaps that are just beginning to become bridged.