Regulation of Blood Pressure by the Calcineurin Homologous Protein‐1

Abstract

Hypertension has high incidence and health care cost. Its treatments are often ineffective; therefore, we are in need of new strategies to prevent, limit or reverse hypertension. Long‐term regulation of blood pressure (BP) has fundamental renal components; in particular, the causes of impaired renal Na+ handling and possible strategies to overcome disturbances in renal Na+ balance in hypertension are not well defined. Recently, we have shown that a Ca2+‐binding protein, the Calcineurin Homologous Protein‐1 (CHP1), is a regulatory binding partner of a key player in the control of Na+ homeostasis, the epithelial brush‐border Na+/H+ exchanger‐3 (NHE3). Here, we proposed that CHP1 expression controls BP as a regulatory co‐factor of NHE3 transport. Indeed, selective renal silencing of Chp1 via renal subcapsular infusion of Chp1 siRNA in Balb/cJ mice significantly reduced NHE3 protein expression (‐50%). Importantly, Chp1 siRNA treated mice had a reduced systolic blood pressure compared to scrambled siRNA treated mice (‐30%). Chp1 siRNA treated mice also had markedly reduced serum Na+ and increased urinary Na+ excretion compared to scrambled siRNA treated mice. Serum K+ and Cl‐ did not change while urinary K+ and Cl‐ excretion were increased in Chp1 siRNA treated mice. Glomerular Filtration Rate estimated by creatinine clearance was reduced in Chp1 treated mice possibly as consequence of tubuloglomerular feedback. This is the first animal model in mammals where the effect of a reduction in CHP1 protein expression in the kidney was studied. Our findings provide new insights into the action of CHP1 on renal tubular Na+ transport and propose CHP1 protein expression as a novel tool to significantly control blood pressure.