Epigenetic Reprogramming of Renal Pendrin Expression via CRISPR-dCas9-

Bartter Syndrome Type III, consequent to biallelic loss-of-function mutations in CLCNKB, remains incurable despite six decades of palliative pharmacotherapy. The syndrome is characterized by profound metabolic alkalosis (arterial pH 7.51–7.58), hypochloremia (serum Cl⁻ 82– 88 mEq/L), and hypokalemia, arising from impaired chloride reabsorption in the thick ascending limb. Current regimens—non-selective cyclooxygenase inhibition, potassium-sparing diuretics, and electrolyte supplementation—fail to restore physiological acid-base equilibrium, are complicated by nephrotoxicity and growth failure, and do not address the fundamental molecular lesion. Pendrin (SLC26A4), an apical Cl⁻/HCO₃⁻ exchanger expressed in renal β-intercalated cells, constitutes an endogenous bicarbonate secretory pathway that remains epigenetically silenced in Bartter syndrome despite persistent hypochloremic stimuli.