Oxidative Stress Causes Renal Angiotensin II Type 1 Receptor Upregulation, Na+/H+ Exchanger 3 Overstimulation, and Hypertension
Oxidative stress modulates angiotensin (Ang) II type 1 receptor (AT1R) expression and function. Ang II activates renal Na+/H+ exchanger 3 (NHE3) to increase sodium reabsorption, but the mechanisms are still elusive. In addition, the upregulation of AT1R during oxidative stress could promote sodium retention and lead to an increase in blood pressure. Herein, we investigated the mechanism of Ang II–mediated, AT1R-dependent renal NHE3 regulation and effect of oxidative stress on AT1R signaling and development of hypertension. Male Sprague-Dawley rats received tap water (control) or 30 mmol/L of l-buthionine-sulfoximine, an oxidant, with and without 1 mmol/L of Tempol, an antioxidant, for 3 weeks. l-Buthionine-sulfoximine–treated rats exhibited oxidative stress and high blood pressure. Incubation of renal proximal tubules with Ang II caused significantly higher NHE3 activation in l-buthionine-sulfoximine–treated rats compared with control. The activation of NHE3 was sensitive to AT1R blocker and inhibitors of phospholipase C, tyrosine kinase, janus kinase 2 (Jak2), Ca2+–dependent calmodulin (CaM), and Ca2+ chelator. Also, incubation of proximal tubules with Ang II caused Jak2-dependent CaM phosphorylation, which led to Jak2-CaM complex formation and increased Jak2-CaM interaction with NHE3. The activation of these signaling molecules was exaggerated in l-buthionine-sulfoximine–treated rats, whereas Tempol normalized the AT1R signaling. In conclusion, Ang II activates renal proximal tubular NHE3 through novel pathways that involve phospholipase C and an increase in intracellular Ca2+, Jak2, and CaM. In addition, oxidative stress exaggerates Ang II signaling, which leads to overstimulation of renal NHE3 and contributes to an increase in blood pressure.
- Received September 2, 2010.
- Revision received September 18, 2010.
- Accepted December 28, 2010.
- © 2011 American Heart Association, Inc.