Epoxyeicosatrienoic Acid Analog EET-A Blunts Development of Lupus Nephritis in Mice

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.

The proteomic landscape of small urinary extracellular vesicles during kidney transplantation

“…Toll‐like receptor 4 (TLR4) signalling has long been investigated as a mediator for renal fibrosis after transplantation and over the course of various nephropathies (Bergler et al., 2012; Pulskens et al., 2010; Pushpakumar et al., 2017; Souza et al., 2015; Zhao, Perez, Lu, George, & Ma, 2014; Zmonarski, Banasik, Madziarska, Mazanowska, & Krajewska, 2019). In contrast to that, derivatives of arachidonic acids and their mimics were shown to exhibit anti‐fibrotic effects and polymorphisms in their CYP‐dependent metabolism to influence susceptibility to renal injury (Gervasini et al., 2015; Hye Khan, Stavniichuk, Sattar, Falck, & Imig, 2019; Yeboah et al., 2016). The overrepresentation of these processes in the donor sample and the 1‐year sample does not necessarily reflect two counter mechanisms.…”

The role of CXCL family members in different diseases

“…Khan et al had explored the ability of arachidonic acid epoxyeicosatrienoic acid (EET) analog to protect kidney and prevent its injury in a SLE mouse model. After a series of analysis they found that SLE mice exhibited remarkable renal chemotaxis and increased renal mRNA expression of CXC chemokines such as CXCL13 and CXCL16 compared to Non SLE mice, whereas EET analog therapy altered this situation so that the mRNA expression levels of CXC chemokines and its receptors as well as immunocytes infiltration associated with kidney was decreased [ 90 ]. Other studies also clearly suggested the critical role of CXCL16 in the pathogenesis of LN and their clinical values as reliable indicator [ 91 , 92 ].…”

Absolute quantification and characterization of oxylipins in lupus nephritis and systemic lupus erythematosus

“…It is the most important factor affecting the mortality of SLE patients. Previous reports have shown that oxylipins, such as EET and PGD2, play very important role in the progression of LN ( 20 , 22 ). Thus, we analyzed the alterations of oxylipins in patients with LN (LN, 33 patients) compared with SLE patients without LN (non-LN, 65 patients) ( Table 1 ).…”

“…Many drugs targeting the oxylipin metabolic enzymes were developed and some clinical trials associated with oxylipin metabolism also showed promising prospects ( 19 ). In SLE, several of oxylipins had been identified to be significantly changed and critical for SLE pathophysiology, including epoxyeicosatrienoic acid (EET), Thromboxane A2 (TXA2), prostaglandin E2 (PGE2) and PGD2 ( 20 – 23 ), suggesting potential utility of oxylipins as candidate biomarkers for SLE diagnosis and clinical treatment. However, there’s still no detailed overview on global oxylipins expression profiles in SLE and whether they were good candidates for clinical usage.…”