Calcium-sensing Receptor Stimulates Luminal K^+-dependent H^+ Excretion in Medullary Thick Ascending Limbs of Henle's Loop of Mouse Kidney
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The calcium-sensing receptor (CaSR) is known well as a sensor of extracellular calcium for regulating parathyroid hormone secretion. CaSR is located along all nephron segments in the kidney. While hypercalcemia strongly enhances urinary acidification, the relationship between CaSR and acid-base metabolism in the kidney is still uncertain. In the present study, we examined whether CaSR activation caused acid secretion in the medullary thick ascending limb (mTAL), which is one of the major nephron segments involved in both mineral and acid-base regulation. The effects of a potent calcimimetic neomycin (Neo) on intracellular pH (pHi) were analyzed in the <i>in vitro</i> miroperfused mouse mTALs. The mTALs were incubated with 2,7-bis-(2-carboxyethyl)-5(6)-carboxyfluoresceine-acetoxymethylester (BCECF-AM) for microfluorescent pHi measurements. In HCO<sub>3</sub><sup>−</sup>/CO<sub>2</sub>-buffered solution, the steady-state pHi was 7.17 ± 0.01 (<i>n</i> = 19). Basolateral Neo at 0.4 mM in basolateral side significantly alkalinized the mTAL cells to 7.28 ± 0.02 (<i>n</i> = 19), while Neo in the lumen had no effect on pHi. Neo in the basolateral side alkalinized the mTALs in the absence of ambient Na<sup>+</sup> and the presence of H<sup>+</sup>-ATPase inhibitor bafilomycin in the lumen, indicating that the effect of Neo is unrelated to Na<sup>+</sup>-dependent acid-base transporters such as Na<sup>+</sup>-H<sup>+</sup> exchangers and Na<sup>+</sup>-HCO<sub>3</sub><sup>−</sup> cotransporter, or to luminal H<sup>+</sup>-ATPase. In contrast, the effect of Neo on pHi was inhibited by K<sup>+</sup> removal or treatment with specific H<sup>+</sup>-K<sup>+</sup>-ATPase (HKa) inhibitors, ouabain and Sch-28080Sch-28080, in the lumen. Our results suggest that hypercalcemia induces urinary acidification partly by stimulating luminal K<sup>+</sup>-dependent H<sup>+</sup>-excretion via CaSR in mouse mTALs.
- Tohoku J. Exp. Med.
Tohoku J. Exp. Med. 216(1), 7-15, 2008-09-01
Tohoku University Medical Press