Role of AVP in the Pathology of Liddle’s Syndrome

Abstract

The epithelial Na+ channel, ENaC, is expressed in the apical plasma membrane of renal principal cells. ENaC activity is rate limiting for sodium reabsorption across the distal nephron and consequently, is the final arbiter of renal sodium excretion. Gain of function mutations in ENaC cause Liddle’s syndrome: an autosomal dominant form of inheritable hypertension. The hypertension of Liddle’s syndrome results from uncontrolled sodium reabsorption via hyperactive ENaC. We hypothesized that improper sodium reabsorption during Liddle’s syndrome may elevate plasma tonicity enough to evoke release of vasopressin (AVP). Indeed, AVP levels are elevated in Liddle’s mice, which have increased ENaC activity as assessed by patch clamp electrophysiology of isolated CNT/CCD. Tolvaptan, an AVP V2 receptor blocker, decreased ENaC activity in Liddle’s mice. Exogenous desmopressin (DDAVP), a V2 receptor specific agonist, had no further effect on ENaC activity in Liddle’s mice. However, DDAVP further increases blood pressure in Liddle’s mice, and this high blood pressure decreases with administration of benzamil, an ENaC blocker. We conclude from these results that ENaC activity is saturated in Liddle’s mice, in part due to elevated AVP levels, but that saturated ENaC activity is still necessary for additional effects of DDAVP on blood pressure in the Liddle’s model. Because DDAVP increases blood pressure but not ENaC activity in Liddle’s mice, we speculate that additional DDAVP‐stimulated water reabsorption further increases blood pressure in this model. Thus, in the Liddle’s mouse, while ENaC activity is saturated, water reabsorption can still respond to additional AVP signaling. Experiments investigating DDAVP effects on AQP2 and AQP3 expression are ongoing and will test whether the hyperosmotic draw of solute from tubular fluid across the collecting duct is saturated in the Liddle’s mouse.Support or Funding InformationThis research was supported by NIH/NIDDK grants R01DK113816 to JDS and R01DK103758 to AP and JDS.