From the Division of Nephrology and Hypertension, and Hypertension Research Center, Georgetown University, Washington, DC (L.L., E.Y.L., Z.L., G.S., M.M., W.J.W., C.S.W.).
Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.H.).
Hypertension. 2018 Nov;72(5):1208-1216. doi: 10.1161/HYPERTENSIONAHA.118.11354.
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 (O) and hydrogen peroxide (HO) by fluorescence microscopy. RRM enhanced the afferent arteriolar gene expression for p47 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 O and HO generation and maximal contractions to Ang II (10 mol/L) that were dependent on O because they were prevented by gene deletion of p47 and on HO because they were prevented by transgenic smooth muscle cell expression of catalase (tg) 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 to 10 mol/L) were paradoxically inhibited by HO and POLDIP2. In conclusion, both O from p47/NOX2 and HO from NOX4/POLDIP2 enhance maximal arteriolar Ang II contractions from RRM mice during high salt, but HO and NOX4/POLDIP2 reduce the sensitivity to lower concentrations of Ang II by >100-fold. Tempol prevents all of these changes in function.
高盐、血管紧张素 II（Ang II）和活性氧会加重慢性肾脏病的进展。我们通过实验验证了一个假说，即高盐摄入会产生特定的活性氧来增强减少肾质量（RRM）的小鼠的入球小动脉对 Ang II 的收缩反应。C57BL/6 小鼠接受了手术 RRM 或假手术，并接受了 6%或 0.4%NaCl 盐饮食 3 个月。通过荧光显微镜测量灌流入球小动脉的 Ang II 收缩反应以及超氧阴离子（O）和过氧化氢（HO）。RRM 增强了入球小动脉 p47 和中性粒细胞氧化酶（NOX）2 的基因表达，而 RRM 小鼠的高盐摄入则增强了血管紧张素 1 型受体、POLDIP2 和 NOX4 的基因表达，并降低了过氧化氢酶。RRM 小鼠的高盐增强了血管活性氧和 HO 的生成以及对 Ang II（10 摩尔/L）的最大收缩反应，这种收缩反应依赖于 O，因为 p47 基因缺失可以防止收缩反应，HO 可以防止过氧化物酶体增殖物激活受体 δ相互作用蛋白 2（POLDIP2）和过氧化物酶体增殖物激活受体 δ相互作用蛋白 2 基因缺失，而由平滑肌细胞表达的过氧化氢酶（tg）和 POLDIP2 基因缺失则可以防止收缩反应。3 个月的 Tempo1 可使血管活性氧和 Ang II 收缩正常化。然而，Ang II 浓度较低（10 至 10 摩尔/L）时，HO 和 POLDIP2 却反常地抑制了血管的收缩反应。综上所述，p47/NOX2 产生的 O 和 NOX4/POLDIP2 产生的 HO 都增强了 RRM 小鼠高盐时入球小动脉对 Ang II 的最大收缩反应，但 HO 和 NOX4/POLDIP2 使 Ang II 浓度降低 100 多倍时对血管的敏感性降低。Tempo1 可预防所有这些功能变化。
