Reduced Expression of Magnesium Transport Proteins in the Distal Convoluted Tubule of Clcnkb-Deficient Mice May Explain Urinary Magnesium Wasting in Classical Bartter Syndrome.

aimThe kidney thick ascending limb (TAL) plays a key role in the transport of sodium, chloride, potassium, calcium, and magnesium. Bartter syndrome is a hypokalemic, salt-losing tubulopathy caused by impaired TAL function. Pathogenic variants in SLC12A1 or KCNJ1 cause antenatal Bartter syndrome, and variants in CLCNKB result in classical Bartter syndrome. Although all variants impair TAL electrolyte transport, their effects on mineral handling differ. In contrast to antenatal forms, classical Bartter syndrome is frequently associated with hypomagnesemia, a feature also found in Gitelman syndrome resulting from pathogenic variants in SLC12A3, expressed in the distal convoluted tubule (DCT). The mechanisms underlying these distinct clinical phenotypes are not understood.

methodsClcnkb- and Slc12a3-deficient mice as well as human kidneys were investigated. The abundance and localization of electrolyte and mineral transporters and stereological parameters were assessed by immunohistochemistry. Gene and protein expression was determined in Clcnkb-deficient mice.

resultsIn human kidney, both ClC-K channels and their essential subunit Barttin were found in TAL, DCT, and collecting system. Clcnkb-deficient mice showed complete ablation of Clcnkb and reduced DCT and connecting tubule volumes. Furthermore, DCT magnesium channels and select basolateral magnesium transporters were markedly reduced in Clcnkb-deficient mice, similar to Slc12a3-deficient mice. In contrast, the overall abundance of calcium transport proteins was largely preserved.

conclusionClC-K channels are expressed in the TAL and DCT in mouse and human kidneys. Clcnkb ablation reduces TRPM magnesium channel expression and DCT tubule volume, providing a likely explanation for the frequently observed hypomagnesemia in classical Bartter syndrome.