Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that causes life threatening renal disease and current therapies are limited with serious side-effects. CYP epoxygenase metabolites of arachidonic acid epoxyeicosatrienoic acids (EETs) demonstrate strong anti-inflammatory and kidney protective actions. We investigated the ability of an orally active EET analog, EET-A to prevent kidney injury in a mouse SLE model. Twenty-weeks old female NZBWF1 (SLE) and age-matched NZW/LacJ (Non SLE) were treated with vehicle or EET-A (10 mg/kg/d, p.o.) for 14 weeks and urine and kidney tissues were collected at the end of the protocol. SLE mice demonstrated marked renal chemotaxis with 30–60% higher renal mRNA expression of CXC chemokine receptors (CXCR) and CXC chemokines (CXCL) compared to Non SLE mice. In SLE mice, the elevated chemotaxis is associated with 5-15-fold increase in cytokine mRNA expression and elevated inflammatory cell infiltration in the kidney. SLE mice also had elevated BUN, serum creatinine, proteinuria, and renal fibrosis. Interestingly, EET-A treatment markedly diminished renal CXCR and CXCL renal mRNA expression in SLE mice. EET-A treatment also reduced renal TNF-α, IL-6, IL-1β, and IFN-γ mRNA expression by 70–80% in SLE mice. Along with reductions in renal chemokine and cytokine mRNA expression, EET-A reduced renal immune cell infiltration, BUN, serum creatinine, proteinuria and renal fibrosis in SLE mice. Overall, we demonstrate that an orally active EET analog, EET-A prevents renal injury in a mouse model of SLE by reducing inflammation.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by abnormality in the immune system
Systemic lupus erythematosus presents with a diverse array of clinical symptoms, which often reflect the consequences of injury to multiple organ systems, such as the kidney, brain, and skin
One of the most well-stablished murine lupus nephritis (LN) models is the female NZBWF1 mice utilized in the current study (Perry et al, 2011)
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by abnormality in the immune system. The success in developing novel and safer therapy for LN is still unsatisfactory and the current therapeutic approaches still depend on high-dose corticosteroids combined with broad-spectrum immunosuppressive agents (Gilkeson, 2015; Jordan and D’Cruz, 2016; Dall’Era, 2017). This lack of novel LN therapies clearly indicates an unmet need for research and development of novel LN treatment options
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