Department of Nephrology and Hypertension Kawasaki Medical School, Kurashiki, Okayama, Japan.
Department of Molecular Oncology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan.
PLoS One. 2018 Oct 3;13(10):e0203823. doi: 10.1371/journal.pone.0203823. eCollection 2018.
Hypertension causes vascular complications, such as stroke, cardiovascular disease, and chronic kidney disease (CKD). The relationship between endothelial dysfunction and progression of kidney disease is well known. However, the relationship between the eNOS-NO pathway and chronic inflammation, which is a common pathway for the progression of kidney disease, remains unexplored. We performed in vivo experiments to determine the role of the eNOS-NO pathway by using eNOS-deficient mice in a hypertensive kidney disease model. All mice were unilateral nephrectomized (Nx). One week after Nx, the mice were randomly divided into two groups: the aldosterone infusion groups and the vehicle groups. All mice also received a 1% NaCl solution instead of drinking water. The aldosterone infusion groups were treated with hydralazine to correct blood pressure differences. After four weeks of drug administration, all mice were euthanized, and blood and kidney tissue samples were collected. In the results, NLRP3 inflammasome activation was elevated in the kidneys of the eNOS-deficient mice, and tubulointerstitial fibrosis was accelerated. Suppression of inflammasome activation by knocking out ASC prevented tubulointerstitial injury in the eNOS knockout mice, indicating that the eNOS-NO pathway is involved in the development of kidney dysfunction through acceleration of NLRP3 inflammasome in macrophages. We revealed that endothelial function, particularly the eNOS-NO pathway, attenuates the progression of renal tubulointerstitial injury via suppression of inflammasome activation. Clinically, patients who develop vascular endothelial dysfunction have lifestyle diseases, such as hypertension or diabetes, and are known to be at risk for CKD. Our study suggests that the eNOS-NO pathway could be a therapeutic target for the treatment of chronic kidney disease associated with endothelial dysfunction.
高血压会导致血管并发症，如中风、心血管疾病和慢性肾脏病（CKD）。内皮功能障碍与肾脏病进展之间的关系是众所周知的。然而，eNOS-NO 途径与慢性炎症之间的关系，即肾脏病进展的共同途径，尚未得到探索。我们通过在高血压肾病模型中使用 eNOS 缺陷小鼠进行体内实验来确定 eNOS-NO 途径的作用。所有小鼠均接受单侧肾切除术（Nx）。Nx 后一周，将小鼠随机分为两组：醛固酮输注组和载体组。所有小鼠还接受 1%NaCl 溶液代替饮用水。醛固酮输注组用肼屈嗪治疗以纠正血压差异。给药四周后，所有小鼠安乐死，采集血液和肾脏组织样本。结果显示，eNOS 缺陷小鼠肾脏中 NLRP3 炎性小体激活增加，肾小管间质纤维化加速。敲除 ASC 抑制炎性小体激活可防止 eNOS 敲除小鼠的肾小管间质损伤，表明 eNOS-NO 途径通过加速巨噬细胞中 NLRP3 炎性小体参与肾功能障碍的发展。我们揭示内皮功能，特别是 eNOS-NO 途径，通过抑制炎性小体激活来减轻肾小管间质损伤的进展。临床上，发生血管内皮功能障碍的患者患有高血压或糖尿病等生活方式疾病，已知其患有 CKD 的风险较高。我们的研究表明，eNOS-NO 途径可能是治疗与内皮功能障碍相关的慢性肾脏病的治疗靶点。
