In mice with a defect of MR in AQP2 expressing cells (AQP2-Gene expression dependent knockout, KO) aldosterone plasma concentration is severely increased. Na⁺ loss under standard diet (std) is efficiently compensated by early connecting tubule, where ENaC is still under the control of the mineralcorticoid receptor. The defective sodium balance can be revealed by dietary Na⁺ depletion and mice show a 1.5fold increase in fractional Na⁺ excretion (Ronzaud et al., JASN, 2007). In first studies we could show, that also the large intestine contributes to the compensation of renal Na⁺ loss under these conditions and that KO animals can reduce their fecal Na⁺ excretion 8fold. ENaC function in large intestine is up-regulated, spatially recruited and, in addition, low sodium diet (lsd) induces an amiloride independent electronic transport indicating a Na⁺ uptake system different from ENaC. We used the Ussing chamber technique to investigate diet and genotype specific alterations in short circuit current (I'sc) in cecum under std and after one week of lsd. Under lsd KO showed a higher amiloride independent I'sc in cecum (-16931mA/cm²) compared to control animals (CTRL) (-8818mA/cm²). Basolateral application of 10mM 293b decreased this I'sc in KO but not in CTRL (DI'sc 33.39.42mA/cm² vs. -0.613.59mA/cm²) indicating the involvement of basolateral KCNQ1 channels. Investigation of the luminal membrane indicate that neither sodium dependent glucose transport nor sodium coupled uptake of fatty acids contribute to this phenomenon. In contrast nonselective cation channels of the TRPM family might be upregulated. Luminal application of 100mM 9-phenanthrol, a blocker of TRPM4, inhibited I'sc in cecum of KO animals (DI'sc 27.23.4mA/cm² vs. -8.614.8mA/cm² in CTRL). These data indicate that mice under challenged Na⁺ homeostasis are able to recruit Na⁺ uptake mechanisms in addition to ENaC in large intestine to support Na⁺ homeostasis.