Abstract: FR-PO118
Increased Gut Permeability in Septic AKI: Role of Na Butyrate (NaB)
Session Information
- AKI: Mechanisms - Inflammation/Sepsis/Remote Injury
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Mullaly, Austin J., Virginia Commonwealth University, North Chesterfield, Virginia, United States
- Lal, Vatsal, Virginia Commonwealth University, North Chesterfield, Virginia, United States
- Denecke, Morgan H., Virginia Commonwealth University, North Chesterfield, Virginia, United States
- Gonzalez, Austin J., Virginia Commonwealth University, North Chesterfield, Virginia, United States
- Ghosh, Siddhartha S., VCU Medical Center, Richmond, Virginia, United States
- Ghosh, Shobha, Virginia Commonwealth University, North Chesterfield, Virginia, United States
- Gehr, Todd W., Virginia Commonwealth University, North Chesterfield, Virginia, United States
Background
Increased intestinal permeability is associated with multiple organ dysfunction syndromes in sepsis. In septic AKI, TLR 4 receptors located on the basolateral side of the intestine can be targeted by systemic lipopolysaccharide (LPS) and cause leaky gut. Intestinal leakage further exaggerates the kidney inflammation and deteriorates AKI. NaB produced by gut microbiota has been shown to curb inflammation and gut permeability. We hypothesize that NaB will protect against LPS-induced leaky gut and ameliorate inflammation and septic AKI.
Methods
Septic AKI was induced by injecting 10 mg/kg LPS (IP). C57Bl6 mice were divided into 3 groups: Control (Ctl), AKI group received LPS (AKI) and treated (TR) group received 300 mg/kg NaB by gavage 30 mins before LPS. Mice were sacrificed after 10 hours. To measure intestinal permeability FITC-Dextran (FD) was given by gavage 2 hours before sacrifice. Blood, kidneys, and colon were harvested for biochemical and immunoblot analysis.
Results
Serum creatinine and BUN of AKI were 0.74±.05 mg/dl and 169±5 mg/dl which measured 2-fold higher than the Ctl (p<0.01). NaB significantly reduced both creatinine and BUN (p<0.05). Serum FD (14±1 µg/ml) of AKI was more than 3-fold higher than Ctl(p<0.01). NaB treatment reduced FD levels by 13% (p<0.05). Compared to Ctl, colonic tight junction protein ZO-1 was significantly reduced in the colon of AKI (p<0.05), but was restored in TR. Inflammatory markers such as high mobility group box protein (HMGB-1), NFkB and IL-1β in the kidney of AKI were 2 to 3 fold higher than Ctl (p<0.05) but NaB treatment decreased them suggesting that NaB can decrease kidney inflammation in LPS induced AKI.
Conclusion
Higher levels of serum FD and loss of intestinal tight junction protein shows that endotoxemia can increase intestinal permeability which may cause leakage of toxic biomolecules from the intestine. LPS can activate inflammatory responses through HMGB-1. NaB activates intestinal alkaline phosphatase which dephosphorylates LPS and renders it inactive. In addition, NaB can act as a HMGB-1 antagonist and a GPR109A agonist, both of which support intestinal barrier integrity. These might be some of the mechanism by which NaB can decrease the inflammatory burden and improve renal function in AKI.