Pendrin Expression Is Significantly Enhanced in Kidneys of NCC KO Mice

Northern hybridization and immunofluorescence labeling indicated that the expression of pendrin is significantly increased in kidneys of NCC KO mice (Vallet et al. 2006; Patel-Chamberlin et al. 2016). In addition to the pendrin working in tandem with ENaC, the sodium-dependent chloride/bicarbonate exchanger (NDCBE) shows expression in the CCD and may participate in sodium absorption (Leviel et al. 2010; Eladari and Hubner 2011).

Similar to pendrin-deficient mice, genetically engineered mice lacking NCC do not display excessive salt wasting under baseline conditions (Schultheis et al. 1998). NCC-deficient mice display enhanced calcium absorption (hypocalciuria) along with magnesium wasting (Schultheis et al. 1998; Loffing et al. 2004); the latter is caused by the downregulation of magnesium-absorbing channel (transient receptor potential ion channel TRPM6) in the DCT and will result in low magnesium concentration in blood (hypomagnesium), recapitulating the common phenotypic presentations in patients with Gitelman syndrome.

Double Knockout of Pendrin and NCC Causes Severe Salt Wasting under Baseline Conditions

Very recent reports have unmasked the basis of incongruity between the mild phenotype in NCC KO or pendrin KO mice, and the role of pendrin and NCC as important players in salt reabsorption in the distal tubule. In these studies, mice with single deletion of NCC and pendrin were cross mated in order to generate mice with double deletion of pendrin and NCC (Soleimani et al. 2012). The pendrin/NCC double KO mice displayed significant salt wasting and developed severe volume depletion, kidney hypoperfusion, and metabolic alkalosis (Soleimani et al. 2012). These studies demonstrate that pendrin and NCC cross compensate for the loss of each other, therefore masking the role that each transporter plays in salt reabsorption under baseline conditions (Soleimani et al. 2012).