title: Calcium-sensing receptor stimulates luminal K+-dependent H+ excretion in medullary thick ascending limbs of Henle's loop of mouse kidney.
abstract: 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 in vitro 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(3)(-)/CO(2)-buffered solution, the steady-state pHi was 7.17 +/- 0.01 (n = 19). Basolateral Neo at 0.4 mM in basolateral side significantly alkalinized the mTAL cells to 7.28 +/- 0.02 (n = 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(+) and the presence of H(+)-ATPase inhibitor bafilomycin in the lumen, indicating that the effect of Neo is unrelated to Na(+)-dependent acid-base transporters such as Na(+)-H(+) exchangers and Na(+)-HCO(3)(-) cotransporter, or to luminal H(+)-ATPase. In contrast, the effect of Neo on pHi was inhibited by K(+) removal or treatment with specific H(+)-K(+)-ATPase (HKa) inhibitors, ouabain and Sch-28080, in the lumen. Our results suggest that hypercalcemia induces urinary acidification partly by stimulating luminal K(+)-dependent H(+)-excretion via CaSR in mouse mTALs.
authors: Department of Medical Informatics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors: Elnur Ilham
authors: EI
authors: Farajov
authors: Tetsuji
authors: T
authors: Morimoto
authors: Ulviyya Fizuli
authors: UF
authors: Aslanova
authors: Naonori
authors: N
authors: Kumagai
authors: Noriko
authors: N
authors: Sugawara
authors: Yoshiaki
authors: Y
authors: Kondo
mesh_terms: D000136:Acid-Base Equilibrium / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016764:Cell Polarity; D006863:Hydrogen-Ion Concentration; D006934:Hypercalcemia / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007424:Intracellular Fluid / Q000187:drug effects; D008138:Loop of Henle / Q000187:drug effects / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009355:Neomycin / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D011188:Potassium / Q000502:physiology*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011522:Protons; D044169:Receptors, Calcium-Sensing / Q000502:physiology*
chemical_list: D007093:Imidazoles; D018942:Macrolides; D011522:Protons; D044169:Receptors, Calcium-Sensing; C035235:Sch 28080; D010042:Ouabain; D006180:Proton-Translocating ATPases; D009355:Neomycin; D011188:Potassium; D002118:Calcium