The eNOS-NO pathway attenuates kidney dysfunction via suppression of inflammasome activation in aldosterone-induced renal injury model mice

• Published in: PloS one 2018-10, Vol.13 (10), p.e0203823-e0203823
• Main Authors: Sogawa, Yuji, Nagasu, Hajime, Itano, Seiji, Kidokoro, Kengo, Taniguchi, Shun'ichiro, Takahashi, Masafumi, Kadoya, Hiroyuki, Satoh, Minoru, Sasaki, Tamaki, Kashihara, Naoki
• Format: Article
• Language: English
• Subjects: Activation; Aldosterone; Analysis; Biology and Life Sciences; Blood; Blood pressure; Cardiovascular diseases; Chronic kidney failure; Complications; Complications and side effects; Cytokines; Development and progression; Diabetes mellitus; Drinking water; Fibrosis; Genetic aspects; Hypertension; In vivo methods and tests; Inflammasomes; Inflammation; Injury prevention; Kidney diseases; Kidneys; Laboratory animals; Macrophages; Medical schools; Medical treatment; Medicine and Health Sciences; Mice; Nephrology; Nitric oxide; Pathogens; Permeability; Physiological aspects; Research and Analysis Methods; Rodents; Sodium chloride; Stroke; Therapeutic applications; Water treatment
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0203823

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.