Figure 515

Effects of hypercalcemia on calcium (Ca) reabsorption in the cortical thick ascending limb (cTAL) of the loop of Henle and urinary concentration. (1) Hypercalcemia stimulates the Ca-sensing receptor (CaSR) of cells in the cTAL. (2) Activation of the G-pro-tein increases intracellular free ionized Ca (Ca2+) by way of the inositol 1,4,5-trisphosphate (IP3) pathway, which increases the activity of the P450 enzyme system. The G-protein also increases activity of phospholipase A2 (PLAa), which increases the concentration of arachidonic acid (AA). (3) The P450 enzyme system increases production of 20-hydroxy-eicosatetraenoic acid (20-HETE) from AA. (4) 20-HETE inhibits hormone-stimulated production of cyclic adenosine monophosphate (cAMP), blocks sodium reabsorption by the sodium-potassium-chloride (Na-K-2Cl) cotransporter, and inhibits movement of K out of K-channels. (5) These changes alter the electrochemical forces that would normally favor the paracellular movement of Ca (and Mg) such that Ca (and Mg) is not passively reabsorbed. Both the lack of movement of Na into the renal interstitium and inhibition of hormonal (eg, vaso-pressin) effects impair the ability of the nephron to generate maximally concentrated urine [3,4,14]. ATP—adenosine triphosphate; PK-C—protein kinase C.

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