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

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

Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats

“…Suppression of NFκB signaling inhibits TNFα-stimulated expression of ICAM-1 and VCAM-1 and the adhesion of monocytes to the human bronchial epithelial cell line [ 36 ]. In cholestasis, TNFα mediates IL-6 release from macrophages to aggravate renal dysfunction [ 7 , 9 , 10 ]. In a sepsis model, pioglitazone reduced LPS-induced TNFα and IL-6 production from mouse macrophages through inhibition of NFκB [ 37 , 38 ].…”

“…Common bile duct ligation (BDL) was conducted on adult male Sprague-Dawley rats (300–350 g), as described previously [ 2 , 5 , 10 , 24 ]. All animal experiments were approved by the Animal Care Committee of the National Yang-Ming Chiao Tung University (YMCU) and conducted in the animal facilities of YMCU with No.…”

“…All rats were anesthetized intraperitoneally with zoletil (50 mg/kg body weight, ip) and fixed in the supine position. The isolated renal perfusion study of the right kidney was conducted as previously described [ 10 , 12 ]. In the rat perfusion system, RVR was recorded using a pressure transducer (Gould, Oxnard, CA, USA) as changes in renal perfusion pressure (RPP) downstream from the pump.…”

“…Endotoxemia-related renal inflammation is characterized by a reduction in RABF in septic rats [ 8 ]. Endotoxin and TNFα/NFκB are involved in the RABF decline and chronic renal dysfunction in bile-duct ligated rats [ 9 , 10 ]. In healthy rats, the infusion of TNFα lowers RABF and increases RVR by inducing vascular inflammation without affecting arterial pressure [ 11 , 12 ].…”

The Role and Mechanism of Histone Deacetylases in Acute Kidney Injury

“…Inflammation is one of the main mechanisms responsible for the progression of AKI. SIRT1 activation can attenuate inflammation by interacting with high-mobility group box 1 (HMGB1) at the deacetylated lysine sites K28, K29, and K30 ( Wei et al, 2019 ), and suppressing pro-inflammatory cytokine (TNF-α, IL-6) production ( Chou et al, 2021) , vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expressions, STAT3/ERK phosphorylation, and nuclear factor kappa-B (NF-κB) activation ( Gao et al, 2014 ). SIRT1 overexpression can suppress the acetylation of NF-κB/p65 at lysine 310 in cisplatin-treated renal tubular cells ( Kim et al, 2019 ).…”