Intestinal SIRT1 Deficiency-Related Intestinal Inflammation and Dysbiosis Aggravate TNFα-Mediated Renal Dysfunction in Cirrhotic Ascitic Mice

International Journal of Molecular Sciences

Ming-Chih Hou¹  Yu-Te Chou¹  Yi-Hsiang Huang¹  Chih-Wei Liu¹  Chia-Chang Huang²  Ming-Wei Lin²  Ueng-Cheng Yang²  Ying-Ying Yang²  Tze-Tze Liu²  Han-Chieh Lin²  Tzu-Hao Li²  Shiang-Fen Huang²  Tzung-Yan Lee³  Hsuan-Miao Liu³ 

[1] Department of Medicine, Taipei Veterans General Hospital, Taipei 11267, Taiwan;Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11267, Taiwan;Graduate Institute of Traditional Chinese Medicine, Chang Guang Memorial Hospital, Linkou 33371, Taiwan;

关键词: cirrhotic ascites;    tumor necrosis factor-α (TNFα);    NAD-dependent deacetylase sirtuin-1 (SIRT1);    intestinal barrier dysfunction;    intestinal dysbiosis;    renal dysfunction;   

DOI  :  10.3390/ijms22031233

来源: DOAJ

【 摘 要 】

In advanced cirrhosis, the TNFα-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 TNFα-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFα-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Systemic and renal hemodynamics, intestinal dysbiosis [cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstrictive response (renal vascular resistance (RVR) and glomerular filtration rate (GFR)) to cumulative doses of TNFα were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. In SIRT1^IEC-KO-BDL-ascitic mice, the worsening of intestinal dysbiosis exacerbates intestinal inflammation/barrier dysfunction, the upregulation of the expressions of intestinal/renal TNFα-related pathogenic signals, higher TNFα-induced increase in RVR, and decrease in GFR in perfused kidney. In intestinal SIRT1 knockout groups, the positive correlations were identified between intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between CDR and RVR, with the positive correlation between CDR and GFR. 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 TNFα-related pathogenic inflammatory signals.

【 授权许可】

Unknown