Epoxyeicosatrienoic Acid Analog Decreases Renal Fibrosis by Reducing Epithelial-to-Mesenchymal Transition

Skibba, Melissa; Khan, M. Mahmud; Kolb, Lauren L.; Yeboah, Michael M.; Falck, John R.; Amaradhi, Radhika; Imig, John D.

doi:10.3389/fphar.2017.00406

Cited by 35 publications

(41 citation statements)

References 44 publications

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“…Inhibition of 5‐LOX, COX‐1, and COX‐2 reduces muscle fibrosis and lipid accumulation after rotator cuff repair . EETs have antifibrotic effects on a variety of fibrotic diseases, including renal fibrosis, liver fibrosis, and myocardial fibrosis . However, the pathogenesis of PF is complex, from early inflammation to late fibrosis, and the suppression of one pathway of ARA is not enough to resist the development of disease .…”

Section: Discussionmentioning

confidence: 99%

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

et al. 2019

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Pulmonary fibrosis (PF) is a senescence-associated disease with poor prognosis. Currently, there is no effective therapeutic strategy for preventing and treating the disease process. Mounting evidence suggests that arachidonic acid (ARA) metabolites are involved in the pathogenesis of various fibrosis. However, the relationship between the metabolism of ARA and PF is still elusive. In this study, we observed a disorder in the cyclooxygenase-2/cytochrome P450 (COX-2/CYP) metabolism of ARA in the lungs of PF mice induced by bleomycin (BLM). Therefore, we aimed to explore the role of COX-2/CYP-derived ARA metabolic disorders in PF. PTUPB, a dual COX-2 and soluble epoxide hydrolase (sEH) inhibitor, was used to restore the balance of COX-2/CYP metabolism. sEH is an enzyme hydrolyzing epoxyeicosatrienoic acids derived from ARA by CYP. We found that PTUPB alleviated the pathological changes in lung tissue and collagen deposition, as well as reduced senescence marker molecules (p16 Ink4a and p53-p21 Waf1/Cip1 ) in the lungs of mice treated by BLM. In vitro, we found that PTUPB pretreatment remarkably reduced the expression of senescence-related molecules in the alveolar epithelial cells (AECs) induced by BLM. In conclusion, our study supports the notion that the COX-2/CYP-derived ARA metabolic disorders may be a potential therapeutic target for PF via inhibiting the cellular senescence in AECs.

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Section: Discussionmentioning

confidence: 99%

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

et al. 2019

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“…Overexpression of collagen is an important link in the formation of renal interstitial fibrosis, and TGF-b1 is the most important regulator of type I collagen (Jiang et al, 2016). Anti-TGF-b is considered as one of the promising methods for anti-fibrosis treatment (Doi et al, 2011). However, the pathological mechanism of organ fibrosis is complex, and there are often multiple links and targets.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Perturbed Metabolic Pathways Associating With Renal Fibrosis and Evaluating Metabolome Changes of Pretreatment With Astragalus polysaccharide Through Liquid Chromatography Quadrupole Time-Of-Flight Mass Spectrometry

et al. 2020

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Renal fibrosis is glomerulosclerosis and renal tubulointerstitial fibrosis caused by the increase of interstitial cells and intercellular substances and the accumulation of extracellular matrix, and is a common pathological manifestation of renal disease progressing to end-stage renal failure. It has proved that Astragalus polysaccharide (AP) has curative effect on renal disease; however, its therapeutic mechanism on renal fibrosis is still unclear. Metabolomics approach provides an opportunity to identify novel molecular biomarkers. The purpose of this study is to study the changes of serum metabolic profile of rats with unilateral tubal ligation and replication of renal fibrosis model and the therapeutic effect of AP on it. The blood samples of rats in the control group, renal fibrosis model group, and AP treatment group collected on the 21st day were analyzed by metabolomics method based on UPLC-Q-TOF-MS. Principal component analysis (PCA) showed that clustering was obvious and significantly separated, and paired partial least squares discriminant analysis (OPLS-DA) was used for further analysis. Combined with the network databases such as HMDB and KEGG and a large number of literatures, 32 potential biomarkers related to renal fibrosis were preliminarily screened out and further verified by MS/MS secondary debris information. After pretreatment with AP, 20 biomarkers were significantly regulated, and correlated with phenylalanine, tyrosine, and tryptophan biosynthesis, phenylalanine metabolism, arachidonic acid metabolism, etc. It also revealed the metabolic changes of renal fibrosis and intervention effect of AP. These data uncover a link between metabolism and the molecular mechanism with potential implications in the understanding of the intervention effect of AP. Conclusively, UPLC-Q

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“…Orally active EET analogs protect the kidney from chronic injury through combined anti-inflammatory, anti-apoptotic, and anti-fibrotic mechanisms (142–144). The ability for EET-A to mitigate radiation nephropathy caused by total body irradiation (TBI) indicates that EET analog intervention prevents progression of chronic kidney disease (142).…”

Section: Therapeutic Application Of Orally Active Eet Agonists In Prementioning

confidence: 99%

“…The anti-fibrotic mechanism by which EET-A diminishes chronic kidney disease was evaluated. EET-A treatment for 10 days produces clear anti-fibrotic actions by decreasing renal collagen positive area, kidney hydroxyproline content, and renal α-smooth muscle actin levels by 50–70% (144). A critical factor that contributes to kidney fibrosis is renal epithelial to mesenchymal transition (EMT) and involves renal epithelial cells that undergo phenotypic and functional changes to myofibroblasts (145).…”

Section: Therapeutic Application Of Orally Active Eet Agonists In Prementioning

confidence: 99%

“…A critical factor that contributes to kidney fibrosis is renal epithelial to mesenchymal transition (EMT) and involves renal epithelial cells that undergo phenotypic and functional changes to myofibroblasts (145). In UUO mice, the anti-fibrotic actions of EET analog treatment are due to a marked decline in E-cadherin transcription factors and renal EMT signaling pathways (144). Taken together, these findings demonstrate that EET analogs prevent and treat kidney diseases through direct renal epithelial cellular protective actions.…”

Section: Therapeutic Application Of Orally Active Eet Agonists In Prementioning

confidence: 99%

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Orally Active Epoxyeicosatrienoic Acid Analogs

Campbell

Imig

Schmitz

et al. 2017

Journal of Cardiovascular Pharmacology

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Biologically active epoxyeicosatrienoic acid regioisomers (EETs) are synthesized from arachidonic acid by cytochrome P450 epoxygenases of endothelial, myocardial and renal tubular cells. EETs relax vascular smooth muscle and decrease inflammatory cell adhesion and cytokine release. Renal EETs promote sodium excretion and vasodilation to decrease hypertension. Cardiac EETs reduce infarct size following ischemia-reperfusion injury and decrease fibrosis and inflammation in heart failure. In diabetes, EETs improve insulin sensitivity, increase glucose tolerance and reduce the renal injury. These actions of EETs emphasize their therapeutic potential. To minimize metabolic inactivation, 14,15-EET agonist analogs with stable epoxide bioisosteres and carboxyl surrogates were developed. In pre-clinical rat models, a subset of agonist analogs, termed EET-A, EET-B and EET-C22, are orally active with good pharmacokinetic properties. These orally active EET agonists lower blood pressure and reduce cardiac and renal injury in spontaneous and angiotensin hypertension. Other beneficial cardiovascular actions include improved endothelial function and cardiac anti-remodeling actions. In rats, EET analogs effectively combat acute and chronic kidney disease including drug- and radiation-induced kidney damage, hypertension and cardiorenal syndrome kidney damage, and metabolic syndrome and diabetes nephropathy. The compelling pre-clinical efficacy supports the prospect of advancing EET analogs to human clinical trials for kidney and cardiovascular diseases.

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Epoxyeicosatrienoic Acid Analog Decreases Renal Fibrosis by Reducing Epithelial-to-Mesenchymal Transition

Cited by 35 publications

References 44 publications

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

Identification of the Perturbed Metabolic Pathways Associating With Renal Fibrosis and Evaluating Metabolome Changes of Pretreatment With Astragalus polysaccharide Through Liquid Chromatography Quadrupole Time-Of-Flight Mass Spectrometry

Orally Active Epoxyeicosatrienoic Acid Analogs

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