Figure 1.
(A) Expression sites for key transporters and regulatory factors along the distal nephron. Traditional and alternative naming conventions of distal nephron segments are shown (alternative convention proposed by Yang et al.18). TAL, thick ascending limb; DCT, distal convoluted tubule; CNT, connecting tubule; CNTe, early CNT; CNTas, aldosterone sensitive CNT; CCD, cortical collecting duct; NKCC2, Na+:K+:Cl- cotransporter NKCC; NCC, Na+:Cl- cotransporter; γENaC, Epithelial Na+ channel ENaC, γ subunit; AQP2: aquaporin 2; 11HSD2: 11-beta-hydroxysteroid dehydrogenase type 2; MR, mineralocorticoid receptor. (B) Changes in NCC activity affect the structure of the distal nephron. Increased activity of NCC is associated with DCT growth and deceased CNT volume, whereas decreased NCC activity is associated with reduced DCT volume and CNT/CD growth.22,31,67,69 (C) DCT model showing NCC regulation by extracellular potassium, ([K+]ec, see text for details). Adrenal zona glomerulosa model showing [K+]ec also directly stimulates aldosterone secretion. (D) Hormones that increase intracellular [cAMP] stimulate NCC activity through signaling pathways that depend on PKA activation. Active PKA phosphorylates WNK4 in sites that promote kinase activation. In addition, PKA phosphorylates the PP1 regulatory subunit I1, a phosphorylation event that allows I1 to repress PP1 activity towards WNK4 and perhaps towards SPAK/OSR1 and NCC.