Mechanisms of paracellular transport of magnesium in intestinal and renal epithelia

Abstract

Magnesium is the fourth most abundant cation in the body. It plays a critical role in many biological processes, including the process of energy release. Paracellular transport of magnesium is mandatory for magnesium homeostasis. In addition to intestinal absorption that occurs in part across the paracellular pathway, magnesium is reabsorbed by the kidney tubule. The bulk of magnesium is reabsorbed through the paracellular pathway in the proximal tubule and the thick ascending limb of the loop of Henle. The finding that rare genetic diseases due to pathogenic variants in genes encoding specific claudins (CLDNs), proteins located at the tight junction that determine the selectivity and the permeability of the paracellular pathway, led to an awareness of their importance in magnesium homeostasis. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is caused by a loss of function of CLDN16 or CLDN19. Pathogenic CLDN10 variants cause HELIX syndrome, which is associated with a severe renal loss of sodium chloride and hypermagnesemia. The present review summarizes the current knowledge of the mechanisms and factors involved in paracellular magnesium permeability. The review also highlights some of the unresolved questions that need to be addressed. K E Y W O R D Sclaudin, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, HELIX syndrome, paracellular ion transport, tight junction Magnesium (Mg) a is the fourth most abundant cation in vertebrates and the second most abundant intracellular cation. Mg homeostasis is mandatory as Mg 2+ is involved in many biological processes.Mg 2+ plays a critical role in the release of chemical energy: Adenosine triphosphate (ATP) is formed by Mg-dependent oxidative phosphorylaa Mg 2+ , free magnesium; Mg, elemental magnesium, including free magnesium and magnesium stably bound to anions, proteins, or nucleic acids.

Identification of Modifier Gene Variants Overrepresented in Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis Patients With a More Aggressive Renal Phenotype

“…Data on CLDN17 is scarce in the scientific literature and the GWAS catalog filter applied in our prioritization pipeline failed to identify this gene as a candidate for further analysis. However, claudins play a critical role on FHHNC and CLDN17 protein, but not RNA, has been described to be present in mouse and human proximal tubules 6 , therefore we decided to include it in our prioritized SKAT-O gene list. A crucial role for CLDN17 in renal function via the regulation of serum electrolytes and tissue reactive oxygen species levels has been recently reported 43 .…”

“…Disease loss-offunction causing mutations have been identified in the tight junction (TJ) proteins claudin 16 (CLDN16) 3 and 19 (CLDN19) 4 . Both proteins are co-expressed in the TJ of the thick ascending limb of Henle’s loop and form a paracellular cation-selective pore that induces a NaCl gradient and a lumen-positive transepithelial voltage driving Ca 2+ and Mg 2+ reabsorption 5,6 . Additionally, CLDN19 is also expressed in the retinal epithelium and a subset of FHHNC patients with CLDN19 mutations develop severe ocular impairment 4 .…”

Claudin‐19 localizes to the thick ascending limb where its expression is required for junctional claudin‐16 localization

“…[1][2][3] In the TAL, some 25% of the filtered calcium and approximately 60% of the filtered magnesium is reclaimed. [1][2][3] The distal convoluted tubule (DCT) and connecting tubule reabsorb the remainder of calcium and magnesium via transcellular routes and only 1-2% is excreted into the final urine. 1,2,4 The understanding of paracellular transport has garnered substantial interest following the identification of specific claudin proteins.…”

“…Both minerals are reabsorbed via paracellular pathways in the proximal tubule and the thick ascending limb (TAL). In the proximal tubule, about 65% of the filtered calcium and approximately 20% of the filtered magnesium is reabsorbed via paracellular shunt pathways 1–3 . In the TAL, some 25% of the filtered calcium and approximately 60% of the filtered magnesium is reclaimed 1–3 .…”

“…In the proximal tubule, about 65% of the filtered calcium and approximately 20% of the filtered magnesium is reabsorbed via paracellular shunt pathways 1–3 . In the TAL, some 25% of the filtered calcium and approximately 60% of the filtered magnesium is reclaimed 1–3 . The distal convoluted tubule (DCT) and connecting tubule reabsorb the remainder of calcium and magnesium via transcellular routes and only 1–2% is excreted into the final urine 1,2,4 .…”