Location of Na-Cl transporters and their regulatory proteins along the aldosterone-sensitive distal nephron. Sodium balance is ultimately achieved in this part of the renal tubule by fine aldosterone-mediated regulation of apically located Na-Cl cotransporters in the distal convoluted tubule (DCT); the epithelial sodium channel (ENaC) in the collecting duct (CD), connecting tubule (CNT), and overlapping expression in the distal convoluted tubule 2 (DCT2); and the aquaporin water transporter 2 (AQP2), which are all limiting factors in transepithelial fluid reabsorption (see review in ref. 11). The aldosterone-sensitive distal nephron expresses genes needed for the specificity of the aldosterone signaling cascade, i.e. the mineralocorticoid receptor (MR) and 11-βHSD2, an enzyme that protects MR from illicit occupation by cortisol. Mutations in these genes also cause severe salt-sensitive hypertensive phenotypes (see recent reviews in refs. 2 and 12). TAL, thin ascending limb; CCD, cortical collecting duct; NKCC2, Na-K-2Cl cotransporter; SGK1, serum glucocorticoid–regulated kinase. Figure adapted with permission from Kriz and Kaissling (13), and Loffing and Kaissling (11).