ena-STUDY-NATIONAL YANG-MING UNIVERSITY-08-12-2020-08:44:19:211-26
Intestinal SIRT1 deficiency-related intestinal inflammation and dysbiosis  aggravate TNF-alpha-mediated renal dysfunction in cirrhotic ascitic mice
Background/Aim: In advanced cirrhosis, the TNF?-mediated intestinal inflammation and bacteria dysbiosis, are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNF?-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFa-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Methods: Systemic and renal hemodynamics, intestinal dysbiosis [low cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstriction response [increased renal vascular resistance (RVR) and decreased glomerular filtration rate (GFR)] to cumulative doses of TNF-alpha were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. Results: In  SIRT1(IEC-KO) - BDL-ascitic mice, the worsening of intestinal dysbiosis further deteriorates intestinal inflammation/barrier dysfunction, upregulates expressions of intestinal/renal TNF-alpha-related pathogenic signals, higher TNF-alpha-induced decrease in RBF, increase in RVR, and decrease in GFR in perfused kidney, and aggravates the severity of renal dysfunction [increased serum creatinine and RVR, decreased renal blood flow (RBF), GFR and urine output, and hyponatremia]. In intestinal SIRT1 knockout groups, the positive correlations were identified between the data of intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between the data of CDR and the data of RVR as well as the positive correlation between the data of the CDR and the data of the GFR. Conclusions: In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNF-alpha-related pathogenic inflammatory signals.
Background/Aim: In advanced cirrhosis, the TNF?-mediated intestinal inflammation and bacteria dysbiosis, are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNF?-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFa-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Methods: Systemic and renal hemodynamics, intestinal dysbiosis [low cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstriction response [increased renal vascular resistance (RVR) and decreased glomerular filtration rate (GFR)] to cumulative doses of TNF-alpha were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. Results: In  SIRT1(IEC-KO) - BDL-ascitic mice, the worsening of intestinal dysbiosis further deteriorates intestinal inflammation/barrier dysfunction, upregulates expressions of intestinal/renal TNF-alpha-related pathogenic signals, higher TNF-alpha-induced decrease in RBF, increase in RVR, and decrease in GFR in perfused kidney, and aggravates the severity of renal dysfunction [increased serum creatinine and RVR, decreased renal blood flow (RBF), GFR and urine output, and hyponatremia]. In intestinal SIRT1 knockout groups, the positive correlations were identified between the data of intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between the data of CDR and the data of RVR as well as the positive correlation between the data of the CDR and the data of the GFR. Conclusions: In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNF-alpha-related pathogenic inflammatory signals.