Molecular mechanisms underlying paracellular calcium and magnesium reabsorption in the proximal tubule and thick ascending limb

Abstract

Calcium and magnesium are the most abundant divalent cations in the body. The plasma level is controlled by coordinated interaction between intestinal absorption, reabsorption in the kidney, and, for calcium at least, bone storage and exchange. The kidney adjusts urinary excretion of these ions in response to alterations in their systemic concentration. Free ionized and anion-complexed calcium and magnesium are filtered at the glomerulus. The majority (i.e., >85%) of filtered divalent cations are reabsorbed via paracellular pathways from the proximal tubule and thick ascending limb (TAL) of the loop of Henle. Interestingly, the largest fraction of filtered calcium is reabsorbed from the proximal tubule (65%), while the largest fraction of filtered magnesium is reclaimed from the TAL (60%). The paracellular pathways mediating these fluxes are composed of tight junctional pores formed by claudins. In the proximal tubule, claudin-2 and claudin-12 confer calcium permeability, while the exact identity of the magnesium pore remains to be determined. Claudin-16 and claudin-19 contribute to the calcium and magnesium permeable pathway in the TAL. In this review, we discuss the data supporting these conclusions and speculate as to why there is greater fractional calcium reabsorption from the proximal tubule and greater fractional magnesium reabsorption from the TAL.

Furosemide rescues hypercalciuria in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis model

“…Furosemide‐induced diuresis and volume contraction may trigger the release of cAMP‐generating hormones such as vasopressin or parathyroid hormone (PTH) followed by increase in intracellular cAMP levels and stimulation of protein kinase A‐dependent pathways 47 . Since PTH may act via both, intracellular cAMP or Ca 2+ release, 34,47,48 exact mechanisms that trigger PMCA and TRPV5 stimulation in response to furosemide remain to be clarified. In addition, chronic furosemide administration may further affect TRPV5 activity by modulation of the urinary pH 49,50 …”

“…8,33 Apart from Cldn2, Cldn12 has also been implicated in reabsorption of divalent cations in the proximal tubule. 33 Although the impact of Cldn12 on the calcium reabsorption appears to be lower compared to Cldn2, 8,34,35 the contribution of Cldn12 may be compensatory increased in Cldn16-deficiency. This potential mechanism should be addressed in future studies.…”

Effects of parathyroid hormone on renal tubular calcium and phosphate handling

“…The majority of free ionized calcium filtered at the glomerulus is reabsorbed by the proximal tubule (~2/3rds) (Figure 1). 22 This occurs through a predominantly, at least 90%, paracellular pathway 23 . There is a small amount of transcellular calcium reabsorption that occurs in the straight portion of the proximal tubule, perhaps mediated by a voltage‐gated calcium channel 24–26 .…”

“…The molecular players contributing to passive paracellular calcium reabsorption from the proximal tubule have largely been delineated over the last decade 23 . Apical sodium entry into proximal tubule epithelium is predominantly contributed by the sodium proton exchanger isoform 3 (NHE3), 29 with basolateral efflux mediated by a combination of the Na + K + ATPase and NDBCE1.…”

“…The molecular identity of the pathway enabling paracellular calcium reabsorption in the proximal tubule has recently been elucidated (Figure 2). 23 Paracellular permeability or barrier properties of an epithelium are contributed by the tight junction family of proteins called claudins. These proteins form interactions between themselves in the tight junction of the same epithelial cell and with claudins in the junction of the adjacent epithelial cell.…”