Renal TRPM6 but not Kv1.1 is required for magnesium homeostasis in mice

The distal convoluted tubule (DCT) reabsorbs only ~10% of the filtered magnesium but fine-tunes the amount excreted in urine. DCT magnesium reabsorption is thought to occur via the TRPM6/7 channel with genetic causes of hypomagnesemia affecting this segment. However, the importance of the renal TRPM6 channel subunit in magnesium homeostasis is unclear due to discrepant findings in renal tubule-specific knockout mice. Furthermore, the apical potassium channel Kv1.1 has been proposed to provide the drive for magnesium entry into the DCT through TRPM6/7. However, most patients with mutations in KCNA1, encoding Kv1.1, have not been reported to present with hypomagnesemia, raising questions regarding its role in magnesium homeostasis. We sought to clarify the importance of TRPM6 and Kv1.1 in renal magnesium handling. We generated mice with inducible DCT-specific TRPM6 knockout (DCT-TRPM6 KO) or renal tubule Kv1.1 knockout (tubule-Kv1.1 KO). Plasma Mg2+ and other blood chemistry parameters were determined. For Kv1.1, additional measurements including GFR, lithium clearance, and diuretic response tests were performed. Disruption of TRPM6 expression was confirmed by Western blot analysis on kidney lysates. DCT-TRPM6 KO displayed lower plasma Mg2+ on diets with normal (0.21% w/w) (control 0.88 mmol/L ± 0.10 versus DCT-TRPM6 KO 0.49 mmol/L ± 0.09, p< 0.0001) or reduced (0.08% w/w) (control 0.92 mmol/L ± 0.08 versus DCT-TRPM6 KO 0.50 mmol/L ± 0.05, p< 0.0001) magnesium content. In contrast, plasma Mg2+ did not differ to controls in tubule-Kv1.1 KO mice on diets containing 0.08% w/w or 0.04% w/w magnesium. There were no differences in other blood chemistry values for either model. GFR, lithium clearance, and natriuretic responses to furosemide, hydrochlorothiazide, or amiloride did not differ in tubule-Kv1.1 KO mice. Immunofluoresence, validated with tubule-Kv1.1 KO mice, revealed Kv1.1 expression in glomeruli and along the S3 segment of the proximal tubule, but not along DCT. RNAScope on human sections revealed a similar pattern of Kv1.1 expression, with co-localization with the S3 marker SGLT1 but not the DCT marker parvalbumin. Our data show that renal TRPM6 plays a critical role in magnesium homeostasis under baseline conditions. In contrast, Kv1.1 is not expressed along DCT and is not required for magnesium homeostasis even under reduced magnesium intake. Loss of Kv1.1 had no significant effect on renal function at baseline. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.