High Salt Enhances Reactive Oxygen Species and Angiotensin II Contractions of Glomerular Afferent Arterioles From Mice With Reduced Renal Mass

• Type of Material: Article
• Authors: Lingli Li, Georgetown University; En Yin Lai, Georgetown University; Zaiming Luo, Georgetown University; Glenn Solis, Georgetown University; Margarida Mendonca, Georgetown University; Kathy Griendling, Emory University; Anton Wellstein, Georgetown University; William J. Welch, Georgetown University; Christopher S. Wilcox, Georgetown University
• Language: English
• Date: 2018-11-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11354
• Title of Journal or Parent Work: Hypertension
• ISSN: 0194-911X
• Volume: 72
• Issue: 5
• Start Page: 1208
• End Page: 1216
• Grant/Funding Information: This work was supported by grants from the National Institute for Diabetes, Digestive Disorders and Kidney Disease (DK49870 and DK36079) and the National Heart, Lung and Blood Institute (HL68086) of the NIH; and by funds from the George E. Schreiner Chair of Nephrology; the Smith-Kogod Family Foundation; and the Georgetown University Hypertension Research Center; and by grants to En Yin Lai from National Nature Science Foundation of China (31471100 and 31671193).
• Keywords: reactive oxygen species; MOUSE MODEL; tempol; angiotensin II; Life Sciences & Biomedicine; ISCHEMIA-REPERFUSION INJURY; CKD PROGRESSION; SUPEROXIDE-DISMUTASE; Science & Technology; superoxides; hydrogen peroxide; BLOOD-PRESSURE; NADPH OXIDASE; Peripheral Vascular Disease; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; INFUSED RABBITS; AT(1) RECEPTORS; Cardiovascular System & Cardiology
• Research Categories: Biology, Physiology; Health Sciences, Medicine and Surgery

Abstract

High salt, Ang II (angiotensin II), and reactive oxygen species enhance progression of chronic kidney disease. We tested the hypothesis that a high salt intake generates specific reactive oxygen species to enhance Ang II contractions of afferent arterioles from mice with reduced renal mass (RRM). C57BL/6 mice were subjected to surgical RRM or sham operations and received 6% or 0.4% NaCl salt diet for 3 months. Ang II contractions were measured in perfused afferent arterioles and superoxide (O2-) and hydrogen peroxide (H2O2) by fluorescence microscopy. RRM enhanced the afferent arteriolar gene expression for p47phox and neutrophil oxidase (NOX) 2 and high salt intake in RRM mice enhanced gene expression for angiotensin type 1 receptors, POLDIP2 and NOX4 and reduced catalase. High salt in mice with RRM enhanced arteriolar O2- and H2O2 generation and maximal contractions to Ang II (10-6 mol/L) that were dependent on O2- because they were prevented by gene deletion of p47phox and on H2O2 because they were prevented by transgenic smooth muscle cell expression of catalase (tgCAT-SMC) and POLDIP2 gene deletion. Three months of tempol normalized arteriolar reactive oxygen species and Ang II contractions. However, arteriolar contractions to lower concentrations of Ang II (10-8 to 10-11 mol/L) were paradoxically inhibited by H2O2 and POLDIP2. In conclusion, both O2- from p47phox/NOX2 and H2O2 from NOX4/POLDIP2 enhance maximal arteriolar Ang II contractions from RRM mice during high salt, but H2O2 and NOX4/POLDIP2 reduce the sensitivity to lower concentrations of Ang II by >100-fold. Tempol prevents all of these changes in function.