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

The renal distal convoluted tubule (DCT) plays a key role in magnesium homeostasis, with genetic and drug-induced causes of hypomagnesemia affecting this segment. The importance of the renal transient receptor potential melastatin (TRPM) 6 channel subunit of the TRPM6/7 magnesium channel in magnesium homeostasis is unclear due to discrepant findings in knockout mice. Furthermore, the apical voltage-gated potassium channel subtype 1.1 (Kv1.1) has been proposed to drive magnesium entry through TRPM6/7 along DCT, with limited experimental evidence. To clarify the roles of TRPM6 and Kv1.1, we generated mice with inducible DCT-specific TRPM6 knockout (DCT-TRPM6 KO) or renal tubule Kv1.1 knockout (tubule-Kv1.1 KO). Using a newly generated antibody, we found that TRPM6 expression is restricted to early DCT (DCT1), consistent with single-cell transcriptomic data. DCT-TRPM6 KO displayed lower plasma [Mg²⁺] on diets with normal (0.21% wt/wt) or reduced (0.08% wt/wt) magnesium content. In contrast, plasma [Mg²⁺] did not differ from controls in tubule-Kv1.1 KO mice on diets containing 0.08% wt/wt or 0.04% wt/wt magnesium. There were no differences in other blood chemistry values for either knockout. Glomerular filtration rate (GFR), lithium clearance, and natriuretic responses to furosemide, hydrochlorothiazide, or amiloride did not differ in tubule-Kv1.1 KO mice. Immunofluorescence and single-molecule fluorescent in situ hybridization revealed Kv1.1 expression in mouse and human glomeruli and along the S3 segment of the proximal tubule, but not along DCT. In summary, renal TRPM6 plays a critical role in magnesium homeostasis under baseline conditions. Kv1.1 is not expressed along DCT and is not required for magnesium homeostasis or normal renal function at baseline.NEW & NOTEWORTHY Using DCT-specific TRPM6 and renal tubule Kv1.1 knockout mice, we found that TRPM6, but not Kv1.1, is expressed in DCT and is required to maintain plasma [Mg²⁺]. In mouse and human kidney, Kv1.1 is expressed in glomerular epithelia and the S3 segment of the proximal tubule. Renal tubule disruption of Kv1.1 did not affect blood chemistry, GFR, lithium clearance, or diuretic responses at baseline. Our data clarify the roles of these channels in the kidney.