Net K Secretion in Thick Ascending Limb in Mice on Low Na High K Diet

Abstract

A low Na and high K diet is considered a healthy choice for its cardiovascular benefits. Understanding the effect of such diet on renal handling of K is imperative for choosing effective diuretics and preventing hyperkalemia and hypokalemia. Wild‐type (WT) and Ca‐activated K channel (BK) β4‐subunit knockout mice (KO) were fed either control or a low Na high K diet (LNaHK) for 7‐10 days (all groups: N 蠅 4). Urine samples were collected from mice in metabolic cages 12 hours after intra‐peritoneal injection of vehicle (veh), furosemide (furo), amiloride (amil), or furo + amil. In WT on a control diet, the urinary K excretion (UKV, μmol/day) was higher in furo‐treated mice compared to veh due to increased distal flow (furo: 390 ± 48 vs veh: 297 ± 26). However, in WT on LNaHK, UKV was significantly lower in furo‐treated mice compared to veh despite increased distal flow (furo: 609 ± 113 vs veh: 1057 ± 121). Furo + Amil treatment decreased UKV more than either drug alone in WT on LNaHK (furo + amil: 143 ± 41; furo: 609 ± 113; amil: 413 ± 68). In KO on LNaHK, however, UKV was not different between furo and veh groups (furo: 571 ± 80 vs veh: 464 ± 80). Using HPLC, we found the furosemide concentrations in plasma of both WT and KO mice were 2.3 μM and 1.4 μM 2 hours and 6 hours, respectively, after treatment, which would inhibit the basolateral NKCC1 in the collecting ducts by only 20%. Immunofluorescence staining showed that BK was also expressed in the apical membrane of medullary collecting ducts (MCD) of LNaHK for WT, but not KO. These results suggest that there is a net K secretion in the thick ascending limb of loop of Henle in mice on the LNaHK diet, which is dependent on the BK‐mediated K recycling and high interstitial K concentration in the MCD.