Increased sodium transporters in distal nephron segments are associated with clozapineinduced hypertension

Dopamine receptor subtype 4 (D 4 R) antagonists, such as clozapine, are used in the treatment of schizophrenia. A common side effect of clozapine is hypertension but the mechanism of the clozapine‐induced hypertension is unknown. D 4 R plays an important role in blood pressure (BP) regulation; deletion of the D 4 R gene in mice causes hypertension. To determine if renal mechanisms are involved in clozapine‐induced hypertension, we characterized the distribution of D 4 R in mouse kidney and measured BP, water and sodium balance, and renal protein expression of sodium transporters in clozapine‐ and vehicle‐treated mice. D 4 R (immunocytochemistry) was mainly located in thick ascending limb, distal convoluted tubule and cortical and medullary collecting ducts; there is slight staining of D 4 R in the proximal convoluted but not straight tubule. Clozapine (20mg/kg/day) or vehicle was delivered subcutaneously to adult male C57BL/6J mice for seven days via osmotic mini‐pump (n=5/group). In clozapine‐treated mice, systolic (110±0.5, mm Hg, under anesthesia) and diastolic BPs (76.6±1),) were elevated, relative to vehicle‐treated mice (SBP=97.6±1.6, DBP=69.5±2.3). Food and water intake, body weight, serum electrolytes and creatinine, urine volume, and creatinine clearance were similar in the two groups. The sodium excretion tended to decrease while sodium excretion and blood pressure plot in clozapine‐treated mice was shifted to the right of the vehicle‐treated mice. Renal protein expressions (immunoblotting) of sodium hydrogen exchanger 3 and sodium phosphate cotransporter 2 were similar in clozapine‐ and vehicle‐treated mice. However, the renal protein expressions of sodium potassium 2 chloride cotransporter (180±21, % of control) and sodium chloride cotransporter (171±22% ), and the three subunits of epithelial sodium channel, α (140±7%), β (166±21%) and γ (55 kDa=130±7%, 85kDa=114±10% ), were greater in clozapine‐than vehicle‐treated mice. Renal protein expression of a‐sodium potassium ATPase was also slightly increased (118±4%) in clozapine‐treated mice. These findings suggest that inhibition of D 4 R by clozapine increases sodium transporters in distal nephron segments. Furthermore, a similar increase in the protein expression of sodium chloride cotransporter was also found in the immortalized mouse renal distal convoluted tubule cells in vitro with inhibition of D 4 R with its siRNA and antagonists. Thus, inhibition of renal D 4 R may cause the impaired sodium excretion that may be responsible for the increased blood pressure in clozap‐inetreated mice. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .