Abstract
This study was initiated to determine whether 2 structurally related flavonoids found in Cyclopia subternata-vicenin-2 (VCN) and scolymoside (SCL)-could modulate renal functional damage in a mouse model of sepsis, and to elucidate the relevant underlying mechanisms. The potential of VCN and SCL treatment to reduce renal damage induced by cecal ligation and puncture (CLP) surgery in mice was measured via assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Treatment with either VCN or SCL resulted in elevated plasma levels of BUN and creatinine, and of protein in the urine of mice with CLP-induced renal damage. Moreover, both VCN and SCL inhibited nuclear factor κB activation and reduced the induction of nitric oxide synthase and excessive production of nitric acid. VCN and SCL treatment also reduced the plasma levels of interleukin-6, and tumor necrosis factor-α, reduced lethality due to CLP-induced sepsis, increased lipid peroxidation, and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues. The present results suggest that VCN and SCL protect mice from sepsis-triggered renal injury.
Highlights
Sepsis is a serious infection that causes severe inflammatory responses and is associated with a high level of mortality despite recent advances in critical care (Russell, 2006)
cecal ligation and puncture (CLP) surgery increased nephrotoxic markers levels (Table I), such as blood urea nitrogen (BUN) and creatinine in blood, and protein concentrations in the urine compared to those in the sham-operated group, all of which were reduced by administration of VCN and SCL (0.3, 0.6, or 1.2 mg/kg, 12 h and 50 h after CLP)
We report that: (1) the expression of plasma BUN and creatinine and urine protein levels were increased by CLP, but decreased by VCN and SCL treatment; (2) CLP increased renal tissue injury inflammatory protein markers, and treatment with VCN and SCL reduced these levels; (3) CLPoperated mice showed increased nitric oxide (NO) production in the blood and inducible nitric oxide synthase (iNOS) expression, which was significantly attenuated by treatment with VCN or SCL; and (4) VCN and SCL increased GSH and antioxidant enzyme activity
Summary
Sepsis is a serious infection that causes severe inflammatory responses and is associated with a high level of mortality despite recent advances in critical care (Russell, 2006). Cytokine activation is part of the host defense system against infection, but the excessive production of cytokines can cause extensive damage and multiple organ failure (MOF) (Chaudhry et al, 2013). Sepsis induces the activation of inducible nitric oxide synthase (iNOS) and upregulates the production of nitric oxide (NO) and reactive oxygen species (ROS), leading to cellular toxicity (Parratt, 1998; Symeonides and Balk, 1999). Sepsis-induced MOF may be reduced by inhibiting inflammatory cytokine production and iNOS activity (Draisma et al, 2010; Parratt, 1998; Symeonides, Balk, 1999). New drug candidates that inhibit the production of ROS and inflammatory cytokines may help in the management of severe sepsis or septic shock (Cadenas, Cadenas, 2002; Vincent et al, 2000)
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