Furosemide rescues hypercalciuria in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis model

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 Ca 2+ reabsorption. The loop diuretic furosemide induces compensatory activation in these distal segments. Normally, furosemide enhances urinary calcium excretion via inhibition of the aforementioned cTAL.

Molecular mechanisms of loop diuretics on renal calcium and magnesium transport

“…Mice lacking Cldn16 develop features that mimic FHHNC with urinary wasting of calcium and magnesium. Interestingly, when Cldn16 ‐deficient animals were treated with furosemide, hypercalciuria was blunted, likely due to compensatory mechanisms activated in the DCT and connecting tubule, which were not seen in wild‐type mice receiving similar treatment 11 . Whether furosemide could be employed therapeutically to limit hypercalciuria and the progression of nephrocalcinosis and renal failure in FHHNC patients while minimizing dehydration remains to be tested, but it could be a welcome therapy for these patients.…”

Smart kidneys: Enhance intratubular communication to overcome disease

“…In this issue of Acta Physiologica Kriuchkova and colleagues report that treatment of mice lacking Claudin16, a model for Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC), with the loop diuretics furosemide improves hypercalciuria by enhancing expression of key calcium transport proteins in kidney. 1 Kidneys are central to the homeostasis of calcium and magnesium by regulating their urinary excretion according to dietary intake and metabolic needs. Both active and passive transport mechanisms contribute to the reabsorption of filtered calcium and magnesium and rare monogenic disorders have been extremely helpful in elucidating molecular mechanisms and their contribution to overall renal control of mineral homeostasis.…”

“…In this issue of Acta Physiologica Kriuchkova and colleagues report that treatment of mice lacking Claudin16, a model for Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC), with the loop diuretics furosemide improves hypercalciuria by enhancing expression of key calcium transport proteins in kidney 1 …”

Introducing a special series: Membrane proteins, epithelial transport, and kidney physiology

“…These are just a few highlights and by no means an exhaustive overview of manuscripts published in Acta Physiologica on these topics. Furthermore, many manuscripts have been published within these fields over the latest years, including multiple recent works 9–11 …”

“…Furthermore, many manuscripts have been published within these fields over the latest years, including multiple recent works. [9][10][11] To honor this tradition, we invite you to take part in a special series on the topic of membrane proteins and epithelial transport in physiology and pathophysiology. We look forward to receiving original articles for consideration for publication in this series.…”