Figure 2.

Model of ion transport in the inner stripe of outer medulla (IS-) (A) and in the cortical thick ascending limb of the loop of Henle (C-TAL) (B) and estimated ion concentration (C). The original works used to build the model have been published in References [108,109,110]. NaCl is reabsorbed via the apical cotransporter NKCC2. Most of the potassium that enters the cell recycles back to the lumen via the potassium channel ROMK, thereby hyperpolarizing the apical membrane, while most of the chloride leaves the cell across the basolateral chloride channel CLCKB, resulting in a depolarization of the membrane. Sodium exits the cell via the Na⁺,K⁺-ATPase at the basolateral membrane. The difference in voltage of the two membranes accounts for the lumen positive transepithelial potential difference, the driving force for the paracellular diffusion of divalent cations in the C-TAL and of sodium in the IS-TAL. Claudin (Cldn)16 and Cldn19 may confer a paracellular permeability and selectivity to cations. Cldn14 may interact with Cldn16 and inhibit the Cldn16/Cldn19 complex. It is suggested that Cldn10b drives paracellular NaCl back flux in cortical TAL, adding to the lumen-positive voltage as the paracellular pathway is more permeable to sodium than to chloride. High Ca²⁺ diet and allosteric agonists of calcium-sensing receptor (CaSR) may trigger the expression of Cldn14 via the inhibition of the transcription of two microRNAs miR-9 and miR-374 suppressing Cldn14 gene expression. ^Ø Direct measurement of luminal ion concentration in the TAL is not possible because the segment is inaccessible to micropuncture. Luminal concentrations of Na⁺, chloride (Cl⁻), Mg²⁺ and Ca²⁺ in the early distal convoluted tubule, the segment just downstream the late cortical thick ascending limb (CTAL) have been measured during micropuncture experiments in rodents [111,112,113,114,115,116,117,118,119]. In most studies, concentrations are expressed as a ratio between tubular fluid and plasma ultrafilterable ion concentration. Plasma NaCl is freely filtered, whereas around 60% of Ca and 80% of Mg are ultrafilterable. Luminal ion concentrations in the early medullary thick ascending limb (MTAL) can be estimated based on a Ca²⁺ and Mg²⁺ reabsorption equaling 20–25% and 60–70% of filtered load, respectively and the lack of substantial water reabsorption in the TAL. ^∞ Values of ion concentrations in the cortical interstitial fluid are similar to those in plasma, due to the dense capillary network and high blood flow in the cortex. Those concentrations have been reported in mathematical models except for magnesium (*). Estimates of the luminal and interstitial concentrations of Na⁺, Cl⁻ and Ca²⁺ in the early medullary thick ascending limbs have been published in mathematical models [120,121,122,123,124,125,126].