Intestinal SIRT1 deficiency-related intestinal inflammation and dysbiosis aggravate TNFα-mediated renal dysfunction in cirrhotic ascitic mice

Yu Te Chou, Tze Tze Liu, Ueng Cheng Yang, Chia Chang Huang, Chih Wei Liu, Shiang Fen Huang, Tzu Hao Li, Hsuan Miao Liu, Ming Wei Lin, Ying Ying Yang*, Tzung Yan Lee, Yi Hsiang Huang, Ming Chih Hou, Han Chieh Lin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 SIRT1IEC-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 dysbio-sis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNFα-related pathogenic inflammatory signals.

Original languageEnglish
Article number1233
Pages (from-to)1-19
Number of pages19
JournalInternational Journal Of Molecular Sciences
Volume22
Issue number3
DOIs
StatePublished - 1 Feb 2021

Keywords

  • Cirrhotic ascites
  • Intestinal barrier dysfunction
  • Intestinal dysbiosis
  • NAD-dependent deacetylase sirtuin-1 (SIRT1)
  • Renal dysfunction
  • Tumor necrosis factor-α (TNFα)

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