S3226

S3226 is a highly selective Na⁺/H⁺ exchanger 3 (NHE3) inhibitor that specifically inhibits NHE3-mediated sodium transport. S3226 reduces the reabsorption of water and electrolytes in the proximal convoluted tubule and inhibits blastocyst formation and expansion. In a model of ischemic acute kidney injury, it improves renal function parameters, alleviates tubular damage, and restores intracellular pH homeostasis, thereby exerting a nephroprotective effect without affecting normal tubulo-glomerular feedback regulation. It is commonly used in studies of acute kidney injury and related pathological mechanisms.

NHE3 (rat):0.2 μM

Method: Mouse 2-cell stage embryos were continuously treated with S3226 (1, 5, 10 μM) for 108 hours, and embryo development to the blastocyst stage was observed.
Result: S3226 dose-dependently inhibited blastocyst formation, with blastocyst formation rates of 28% and 2% at 5 μM and 10 μM, respectively, while no significant effect was observed at 1 μM ^[1].
Method: Rat fibroblasts (transfected with rat NHE3) were treated with S3226, and Na⁺/H⁺ exchange activity was measured.
Result: The IC₅₀ of S3226 for inhibiting NHE3 was approximately 0.2 μmol/L ^[2].
Method: Mouse LAP1 fibroblasts (transfected with human NHE1, rabbit NHE2, rat or human NHE3) and pig renal brush border membrane vesicles were treated with S3226, and Na⁺/H⁺ exchange activity was measured.
Result: S3226 selectively inhibited NHE3, with no significant effect on NHE1 and NHE2 ^[3].

Method: Acute renal failure was induced in male Wistar rats by bilateral renal artery clamping for 40 min. S3226 (20 mg/kg) was intravenously infused over 30 min either immediately before clamping or immediately after clamp release. Plasma creatinine, creatinine clearance, and other parameters were measured.
Result: Compared with the control group, the S3226-treated groups showed significantly higher creatinine clearance on day 1 (0.90 and 0.83 vs. 0.30 mL/min/kg, respectively) and significantly lower plasma creatinine. Kidney tissue sections on day 7 revealed markedly reduced tubular necrosis, protein casts, and cellular infiltration ^[2].
Method: Rat renal medullary thick ascending limb segments (from the superficial loop of the last proximal tubule to the earliest distal tubule loop) were microperfused with an artificial luminal fluid containing S3226 (10 or 30 μM), and changes in fluid, Na⁺, and K⁺ reabsorption were measured.
Result: S3226 had no significant effect on fluid, Na⁺, or K⁺ reabsorption in the medullary thick ascending limb segments ^[3].