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Furosemide rescues hypercalciuria in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis model.
- Source :
- Acta Physiologica; Mar2023, Vol. 237 Issue 3, p1-16, 16p, 3 Color Photographs, 3 Charts, 5 Graphs
- Publication Year :
- 2023
-
Abstract
- Aim: Perturbed calcium homeostasis limits life expectancy in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC). This rare disease occurs by loss‐of‐function mutations in CLDN16 or CLDN19 genes, causing impaired paracellular reabsorption of divalent cations along the cortical thick ascending limb (cTAL). Only partial compensation takes place in the ensuing late distal convoluted tubule, connecting tubule, and collecting duct, where the luminal transient receptor potential channel V5 (TRPV5), as well as basolateral plasma membrane calcium ATPase (PMCA) and sodium‐potassium exchanger (NCX1) mediate transcellular Ca2+ reabsorption. The loop diuretic furosemide induces compensatory activation in these distal segments. Normally, furosemide enhances urinary calcium excretion via inhibition of the aforementioned cTAL. As Ca2+ reabsorption in the cTAL is already severely impaired in FHHNC patients, furosemide may alleviate hypercalciuria in this disease by activation of the distal transcellular Ca2+ transport proteins. Methods: Cldn16‐deficient mice (Cldn16−/−) served as a FHHNC model. Wild‐type (WT) and Cldn16−/− mice were treated with furosemide (7 days of 40 mg/kg bw) or vehicle. We assessed renal electrolyte handling (metabolic cages) and key divalent transport proteins. Results: Cldn16−/− mice show higher Ca2+ excretion than WT and compensatory stimulation of Cldn2, TRPV5, and NCX1 at baseline. Furosemide reduced hypercalciuria in Cldn16−/− mice and enhanced TRPV5 and PMCA levels in Cldn16−/− but not in WT mice. Conclusions: Furosemide significantly reduces hypercalciuria, likely via upregulation of luminal and basolateral Ca2+ transport systems in the distal nephron and collecting duct in this model for FHHNC. [ABSTRACT FROM AUTHOR]
- Subjects :
- TRP channels
CARRIER proteins
HYPOMAGNESEMIA
FUROSEMIDE
KIDNEY calcification
Subjects
Details
- Language :
- English
- ISSN :
- 17481708
- Volume :
- 237
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Acta Physiologica
- Publication Type :
- Academic Journal
- Accession number :
- 162202913
- Full Text :
- https://doi.org/10.1111/apha.13927