Thick ascending limb claudins are altered to increase calciuria and magnesiuria in metabolic acidosis
- Authors
- Oh, Il Hwan; Jo, Chor Ho; Kim, Sua; Jo, Sungsin; Chung, Sungjin; Kim, Gheun-Ho
- Issue Date
- Mar-2021
- Publisher
- AMER PHYSIOLOGICAL SOC
- Keywords
- calcium; claudin-16; claudin-19; magnesium; thick ascending limb; tight junction
- Citation
- AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v.320, no.3, pp.F418 - F428
- Indexed
- SCIE
SCOPUS
- Journal Title
- AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
- Volume
- 320
- Number
- 3
- Start Page
- F418
- End Page
- F428
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/1345
- DOI
- 10.1152/ajprenal.00282.2020
- ISSN
- 1931-857X
- Abstract
- Urinary calcium and magnesium wasting is a characteristic feature of metabolic acidosis, and this study focused on the role of the thick ascending limb of Henle's loop in metabolic acidosis-induced hypercalciuria and hypermagnesiuria because thick ascending limb is an important site of paracellular calcium and magnesium reabsorption. Male Sprague-Dawley rats were used to determine the effects of acid loading (by adding NH4Cl, 7.2 mmol/220 g body wt/day to food slurry for 7 days) on renal expression of claudins and then to evaluate whether the results were reversed by antagonizing calcium-sensing receptor (using NPS-2143). At the end of each animal experiment, the kidneys were harvested for immunoblotting, immunofluorescence micros-copy, and quantitative PCR (qPCR) analysis of claudins and the calcium-sensing receptor. As expected, NH4Cl loading lowered urinary pH and increased excretion of urinary calcium and magnesium. In NH4Cl-loaded rats, renal protein and mRNA expression of claudin-16, and claudin-19, were decreased compared with controls. However, claudin-14 protein and mRNA increased in NH4Cl-loaded rats. Consistently, the calcium-sensing receptor protein and mRNA were up-regulated in NH4Cl-loaded rats. All these changes were reversed by NPS-2143 coadministration and were confirmed using immunofluorescence microscopy. Hypercalciuria and hypermagnesiuria in NH4Cl-loaded rats were significantly ameliorated by NPS-2143 coadministration as well. We conclude that in metabolic acidosis, claudin-16 and claudin-19 in the thick ascending limb are down-regulated to produce hypercalciuria and hypermagnesiuria via the calcium-sensing receptor. NEW & NOTEWORTHY This study found that the thick ascending limb of Henle's loop is involved in the mechanisms of hypercalciuria and hypermagnesiuria in metabolic acidosis. Specifically, expression of claudin-16/19 and claudin-14 was altered via upregulation of calcium-sensing receptor in NH4Cl-induced metabolic acidosis. Our novel findings contribute to understanding the regulatory role of paracellular tight junction proteins in the thick ascending limb.
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