From Ion Channels to Blood Pressure: Genetic Disorders of Renal Tubular Transport

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  Fig. 1. Renal tubular electrolyte handling and its impact on BP regulation. Schematic overview of electrolyte transport along the nephron and its contribution to BP regulation. The proximal tubule reabsorbs approximately 60–70% of filtered Na+, followed by 25% reabsorption in the TAL, 5–10% in the DCT, and fine-tuning in the CD. Key transporters include NHE3, SGLT2, AQP1, and Na+/K+-ATPase in the proximal tubule; NKCC2 and ROMK in the TAL, which generate a lumen-positive voltage driving paracellular Ca2+ and Mg2+ reabsorption; NCC in the DCT; and ENaC and AQP2 in the CD, which are regulated by aldosterone and vasopressin, respectively. WNK-SPAK/OSR1 signaling modulates NCC activity in the DCT. Differential regulation of these transporters results in distinct BP outcomes. Enhanced NKCC2, NCC, or ENaC activity leads to Na+ retention and volume expansion, contributing to hypertension, as seen in conditions such as Liddle syndrome, Gordon syndrome, and hyperaldosteronism. Conversely, loss-of-function or inhibition of NKCC2, NCC, or ENaC promotes natriuresis and salt-wasting, associated with hypotension and disorders such as Bartter and Gitelman syndromes. Therapeutic interventions targeting…