Piezo1 Mediates Deoxycorticosterone Acetate-Salt Hypertension Through Renal Epithelial Sodium Channel Activation in the Kidneys

Background: Hypertension is the most important risk factor for cardiovascular, cerebrovascular and renal diseases. Persistent and excessive salt intake damages the kidneys and reduces their ability to excrete sodium, leading to hypertension. Epithelial sodium channel (ENaC), located in the collecting duct principal cells of the kidney, is responsible for the reabsorption of sodium and plays a critical role in the regulation of extracellular fluid volume and consequently blood pressure. The Piezo channel is a type of mechanosensitive cation channel that can be activated by the mechanic stimulation on the cell membrane. The current study aims to investigate whether Piezo1 is involved in regulation of ENaC expression in the kidney and blood pressure in deoxycorticosterone acetate (DOCA)-salt induced hypertensive mice. Methods: Hypertension was induced in mice by subcutaneous implantation of DOCA pellets with 1% NaCl in drinking water, GsMTx4 (antagonist of Piezo1) was given by subcutaneous injection. Male C57BL/6 mice were treated with Piezo1 agonist Yoda1 or β-catenin inhibitor ICG-001 for 2 weeks by intraperitoneal injection. Immortalized mouse cortical collecting duct (mpkCCD) cells were performed with stretch and compression or treated with Yoda1. Results: GsMTx4 markedly decreased DOCA-salt-induced blood pressure in mice, which was associated with reduced the expression of ENaC in the kidney. In mice were injected with Piezo1 agonist Yoda1, the expression of ENaC were significantly increased in the kidney. DOCA-salt treatment significantly upregulated β-catenin expression in the renal cortex, an effect that was markedly attenuated by GsMTx4. Similarly, Yoda1 promoted β-catenin expression, whereas ICG001 suppressed β-catenin and ENaC expression. In mpkCCDs treated with mechanical force or Yoda1, the expression levels of ENaC and β-catenin expression were dramatically upregulated, which was inhibited by GsMTx4 treatment. Yoda1 markedly induced increased Na+ influx in mpkCCD cells, which was significantly blocked by amiloride. ICG001 significantly attenuated the mechanical force or Yoda1-induced upregulation of β-catenin and ENaC subunits. Conclusion: Piezo1 activation induced increased blood pressure likely through upregulating ENaC expression in the kidney of mice with DOCA-salt by activating β-catenin pathway.