Functional Studies of AT1 Antagonist SII Analogues Reveal Selective Cell Signaling and Inhibition of Ang-II Mediated NHE3 Activation

摘要

The angiotensin II (Ang-II) is widely implicated in the development of hypertension and several progressive renal diseases by causing salt and fluid retention and inducing growth and proinflammatory responses. Ang-II has been shown to induce expression of the epithelial sodium channel, the sodium and hydrogen exchanger-3 (NHE3) [1J etc. Ang-II regulates NaC1 reabsorption through both directly acting on the proximal tubule, and indirectly acting on aldosterone secretion. In isolated proximal tubule cells and also brush-border membrane vesicle preps, Ang-II stimulates Na~+ absorption by increasing the activity of NHE3. Previous studies have shown that increased NHE3 function contributes to hypertension observed in rat models induced by Ang-II, and Ang-II stimulates NHE3 activity through increasing NHE3 gene expression levels [2]. These observations suggest the possible role of NHE3 in the pathophysiology of hypertension. The current studies revealed a group of newly designed and synthesized peptides which are selective antagonists of AT1, but are able to recruit β-arrestins, and can block the effect of A-II on NHE3 expression.