Pendrin inhibitor PDSinh-C01 reverses salt-sensitive hypertension and metabolic acidosis in the 5/6 nephrectomy rat model

Abstract

Pharmacological inhibition of the chloride-bicarbonate exchanger pendrin with PDSinh-C01 potentiates the diuretic action of furosemide in healthy mice. Because pendrin contributes to acid-base regulation and blood pressure control, it may represent an attractive therapeutic target in chronic kidney disease (CKD). We investigated whether this pendrin inhibitor improves metabolic acidosis and salt-sensitive hypertension in the 5/6 nephrectomy (5/6Nx) model of CKD. Seven-week-old female Sprague Dawley rats underwent 5/6Nx and implantation of telemetry devices for blood pressure monitoring. All animals received a high-salt (2% NaCl) diet and were randomized (n = 7–9/group) to daily subcutaneous injections for three days of vehicle, PDSinh-C01 (10 mg/kg), furosemide (6 mg/kg), or their combination. The 5/6Nx model recapitulated key features of CKD, including reduced eGFR, hypertension, proteinuria, and hyperchloremic metabolic acidosis. Combination therapy produced the greatest reduction in mean arterial pressure (-11 ± 2 mmHg) compared with vehicle (-3 ± 2 mmHg), furosemide (-6 ± 1 mmHg), or pendrin inhibitor alone (-6 ± 2 mmHg). Furosemide and combination therapy increased urine volume at 6h, whereas only combination therapy increased urine volume at 24h. After three days, the pendrin inhibitor alone and combination therapy increased venous bicarbonate concentrations compared with vehicle (24.5 ± 2.1 and 24.3 ± 1.4 vs. 21.4 ± 1.4 mmol/l). In conclusion, PDSinh-C01 combined with furosemide improves salt-sensitive hypertension in CKD, while PDSinh-C01 alone and in combination with furosemide ameliorates metabolic acidosis. These findings support pendrin as a regulator of electrolyte and acid-base balance and as a potential therapeutic target in CKD.

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