Adequate salt intake is essential for candesartan-treated rats to maintain renal function

Dietary salt restriction and angiotensin-II receptor-1 blockade (ARB) are commonly recommended for patients with renal and cardiovascular diseases. To explore what salt diet was suitable for the ARB users and what measurements predicted acute kidney injury (AKI), we evaluated the impact of low (0.02%, LS), normal (0.4%, NS), and high (2%, HS)-salt diets on renal function and urinary exosomal sodium-hydrogen exchanger-3 (NHE3), sodium-potassium-chloride cotransporter-2 (NKCC2), sodium-chloride cotransporter (NCC), and aquaporin-1 (AQP1) in candesartan-treated rats. All rats were given candesartan (1 mg/kg/day, ip) except as indicated. Relative to NS control, increased serum creatinine (SCr) but decreased creatinine clearance (Ccr) was observed in consecutive LS rats for 7 days with morphological kidney abnormalities. Similar changes at day 3 were observed in the food-switching rats from NS to LS with elevated urine osmolality and creatinine but decreased sodium concentrations. Urinary exosomal NHE3, NKCC2, NCC, and AQP1 were increased in the consecutive LS rats with elevated serum renin, angiotensin-II, and aldosterone. They were increased at day 1 in food-switching rats, 2 days earlier than changes in SCr and Ccr, but similar to urine kidney injury molecule-1. Renal and apical-membranous NHE3 and NKCC2 were increased, but AQP1 was decreased with decreased renal angiotensinogen and angiotensin-II receptor type I (AT1R). A moderate HS reversed the changes seen in food-switching rats in SCr, Ccr, and urinary exosomal measurements and improved the kidney morphological abnormalities. Thus, dietary salt restriction induces a prerenal/reversible kidney injury in candesartan-treated rats; urinary exosomal NHE3, NKCC2, NCC, and AQP1 may serve as early biomarkers for the damage.NEW & NOTEWORTHY Dietary salt restriction in candesartan-treated rats increases serum creatinine and urinary KIM-1 but decreases creatinine clearance with renal morphological abnormalities. Urinary exosomal NHE3, NKCC2, NCC, and AQP1 increase 2 days earlier than the changes of serum creatinine and creatinine clearance. Moderate high-salt diet reverses those changes with improved renal morphology. Extreme salt restriction should be avoided during candesartan treatment; urinary exosomal NHE3, NKCC2, NCC, and AQP1 may serve as early predictors of the acute kidney injury.