Fig. 2

a Normal dynamics of reabsorption in the distal nephron. Most of the Na⁺ and Cl⁻ reaching the distal nephron is reabsorbed by NCC in the distal convoluted tubule (DCT) and a smaller percentage is reabsorbed by ENaC in the connecting tubule (CNT) and cortical collecting duct (CCD). However, ENaC reabsorbs exclusively Na⁺ without Cl⁻ in an electrogenic way, which generates a transepithelial potential of − 40 mV. This negative potential in the tubular light favors the secretion of K⁺ and others protons. b Abnormal dynamics of reabsorption in the distal nephron. In individuals with Gitelman syndrome or other salt-losing tubulopathies with DCT defects, the dysfunction in NCC (by inactivating mutations in SLC12A3 gene) leads to a greater arrival of Na⁺ and Cl⁻ to CNT/CCD, which favors Na⁺ reabsorption mediated by ENaC. Thus, the increase in the electrogenic reabsorption of Na⁺ increases the transepithelial potential and this produces greater tubular secretion of potassium and others protons (as magnesium and sodium) [35, 36]. Abbreviations: CLCNKB: chloride voltage-gated channel Kb; ENaC: epithelial sodium channel; NCC: thiazide-sensitive Na-Cl co-transporter; ROMK: renal outer medullary potassium channel. Figure adapted from Seyberth et al [37]