TY - JOUR
T1 - Epoxyeicosatrienoic acid analog EET-A blunts development of lupus nephritis in mice
AU - Khan, Md Abdul Hye
AU - Stavniichuk, Anna
AU - Sattar, Mohammad Abdul
AU - Falck, John R.
AU - Imig, John D.
N1 - Funding Information:
The Robert A. Welch Foundation provided support to JF (I-0011). A National Institute of Health (NIH) grant to JI (DK103616), a Medical College of Wisconsin Lupus Research Grant to JI, and a Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee Grant to JI and JF.
Publisher Copyright:
© 2007 - 2019 Frontiers Media S.A. All Rights Reserved.
PY - 2019
Y1 - 2019
N2 - 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-a, 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.
AB - 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-a, 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.
KW - Chemokine
KW - EET analog
KW - Inflammation
KW - Lupus nephritis
KW - Mouse
KW - Small lipid mediators
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U2 - 10.3389/fphar.2019.00512
DO - 10.3389/fphar.2019.00512
M3 - Article
C2 - 31133860
AN - SCOPUS:85068851851
SN - 1663-9812
VL - 10
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
IS - MAY
M1 - 512
ER -