In the distal tubule where the voltage in the tubule lumen is electrically negative with respect to blood, reabsorption of Ca++ is entirely active because Ca++ is reabsorbed against its electrochemical gradient (Fig. 36.16 ). Thus Ca++ reabsorption by the distal tubule is exclusively transcellular. Calcium enters the cell across the apical membrane through Ca++-permeable epithelial ion channels (TRPV5). Inside the cell, Ca++ binds to calbindin-D28K. The calbindin-Ca++ complex carries Ca++ across the cell and delivers Ca++ to the basolateral membrane, where it is extruded from the cell primarily by the 3Na+/1Ca++ antiporter (NCX1); however, plasma membrane Ca++-ATPase isoform 1b (PMCA1b) may also contribute. Urinary Na+ and Ca++ excretion usually change in parallel. However, excretion of these ions does not always change in parallel, because reabsorption of Ca++ and Na+ by the distal tubule is independent and differentially • Fig. 36.16 Cellular mechanism of Ca++ reabsorption by the distal tubule. Ca++ is reabsorbed exclusively by a cellular pathway. Ca++ enters the cell across the apical membrane via a Ca++-permeable ion channel (TRPV5). Inside cells, Ca++ binds to calbindin (calbindin-D28K), and the Ca++-calbindin complex diffuses across the cell to deliver Ca++ to the basolateral membrane. Ca++ is transported across the basolateral membrane primarily by a 3 (or 4) Na+/Ca++ antiporter (NCX1) and also by a Ca++-H+-ATPase (PMCa1b). Claudin 8 (CLDN8) is a tight junction protein that is impermeable to Ca++ and thereby prevents the back diffusion of Ca++ across the tight junction into the tubule lumen, which is electrically negative compared to the blood side of the cell.
regulated. For example, thiazide diuretics inhibit Na+ reabsorption by the distal tubule and stimulate Ca++ reabsorption by this segment. Accordingly the net effects of thiazide diuretics are to increase urinary Na+ excretion and reduce urinary Ca++ excretion. Because thiazide diuretics reduce urinary Ca++ excretion, they are often given to reduce urinary [Ca++] in individuals who produce Ca++-containing kidney stones.
Regulation of Urinary Calcium Excretion