Claudin‐2 Null Mice Reveal Increased Renal Transcellular Na Transport And Kidney Oxygen Consumption

Abstract

60% of filtered Na is reabsorbed in renal proximal tubules (PT), 40% of which is transported paracellularly. Claudins are a family of tight junction transmembrane proteins that regulate paracellular permeability. Cation‐selective claudin‐2(cldn2) is expressed in PT. Cldn2 knockout (KO) mice were reported to have markedly decreased PT cation permeability but no Na wasting on regular diet. To evaluate the role of cldn2 in renal salt handling, we placed wild‐type (WT) and cldn2 knockout (KO) mice on a Na deficient diet, and urine was collected every 8 hours. The cldn2 KO mice were able to conserve Na to the same extent as their WT littermates. Quantitative RT‐PCR did not reveal compensatory upregulation of other claudin isoforms. The natriuretic response to the NKCC2 inhibitor, furosemide (25mg/kg ip), was 25% higher in KO compared to WT (P<0.05). Thus, loss of PT Na transport was compensated distally, primarily by a functional increase in transcellular Natransport in the thick ascending limb. We hypothesized that the increased transcellular transport would lead to increased renal oxygen consumption. To test this, we determined the ratio between whole kidney Na reabsorption (TNa) and oxygen consumption (QO2 = RBF X A‐VO2) in WT and KO mice. Cldn2 null mice exhibited lower TNa/QO2 (WT: 7.26±0.66 vs KO: 4.96±0.77 µmol/µmol). In conclusion, our findings suggest that in cldn2 KO mice, loss of PT paracellular Na transport is compensated by increased Na reabsorption by distal transcellular transporters at the expense of decreasing kidney oxygen utilization efficiency.