Soluble epoxide hydrolase inhibition ameliorates proteinuria-induced epithelial-mesenchymal transition by regulating the PI3K-Akt-GSK-3β signaling pathway

Liang, Yaoxian; Jing, Ziyang; Deng, Hui; Li, Zhengqian; Zhuang, Zhen W.; Wang, Song; Wang, Yue

doi:10.1016/j.bbrc.2015.05.020

Cited by 37 publications

(34 citation statements)

References 27 publications

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“…Based on this information, SGK3 could be involved in regulating podocyte injury by affecting the transcriptional levels of podocin. Additional studies are required to address whether and how the SGK3/GSK3 pathway regulates podocin expression and if there are other SGK3 target proteins that may be important for podocyte function and viability (49).…”

Section: Discussionmentioning

confidence: 99%

Lack of serum‐ and glucocorticoid‐inducible kinase 3 leads to podocyte dysfunction

et al. 2018

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Serum- and glucocorticoid-inducible kinase 3 (SGK3) is a downstream mediator of PI3K, which is essential for maintaining the functional integrity of podocytes. However, little is known about the role of SGK3 in podocyte function. Herein, we demonstrated that SGK3 contributes to the maintenance of podocyte integrity. Conditionally immortalized mouse podocyte cells (MPCs) were treated with puromycin aminonucleoside (PAN). PAN treatment inhibited the activity of SGK3 and the expression of podocin. Short hairpin RNA (shRNA)-mediated knockdown of SGK3 also reduced podocin expression in the absence of PAN. Adriamycin (ADR)-treated mice developed proteinuria and had decreased renal glomerular SGK3 expression in comparison to control mice. Consistent with a role for SGK3 in the ADR effect, SGK3 knockout (KO) mice had markedly reduced kidney podocin expression and significantly elevated proteinuria compared with wild-type mice. Electron microscopy revealed that SGK3 KO mice displayed partial effacement of podocyte foot processes. Further, a SGK3 target protein, glycogen synthase kinase-3 (GSK3), was discovered to be dramatically activated in PAN and SGK3 shRNA-treated MPCs and in SGK3 KO mice. Taken together, these data strongly suggest that SGK3 plays a significant role in regulating podocyte function, likely by controlling the expression and activity of GSK3.-Peng, L.-Q., Zhao, H., Liu, S., Yuan, Y.-P., Yuan, C.-Y., Mwamunyi, M.-J., Pearce, D., Yao, L.-J. Lack of serum- and glucocorticoid-inducible kinase 3 leads to podocyte dysfunction.

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Section: Discussionmentioning

confidence: 99%

Lack of serum‐ and glucocorticoid‐inducible kinase 3 leads to podocyte dysfunction

et al. 2018

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“…In addition, epithelial–mesenchymal transition is one of the potential mechanisms contributing to the development of renal fibrosis. Soluble epoxide hydrolase inhibition attenuated urinary protein‐induced epithelial–mesenchymal transition in rat renal proximal tubular epithelial cells by inhibiting phosphatidylinositol 3‐kinase/Akt activation …”

Section: Soluble Epoxide Hydrolase In Kidney Diseasementioning

confidence: 99%

Soluble epoxide hydrolase: A potential target for metabolic diseases

Wang

Zhu

et al. 2016

Journal of Diabetes

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Highlights 1. In the last decade, sEH inhibitors have been found a promising therapeutic approach for combating atherosclerosis and hypertension, presumably from increased endogenous EET levels. 2. Considering the potent beneficial effects of omega-3 PUFAs and sEH inhibitors on metabolic diseases, evaluating the synergistic effect of their combination and learning more about the bioactivities of omega-3 and omega-6 PUFA metabolites will be important. AbstractEpoxyeicosatrienoic acids (EETs), important lipid mediators derived from arachidonic acid, have many beneficial effects in metabolic diseases, including atherosclerosis, hypertension, cardiac hypertrophy, diabetes, non-alcoholic fatty liver disease, and kidney disease. Epoxyeicosatrienoic acids can be further hydrolyzed to less active diols by the enzyme soluble epoxide hydrolase (sEH). Increasing evidence suggests that inhibition of sEH increases levels of EETs, which have anti-inflammatory effects and can prevent the development of hypertension, atherosclerosis, heart failure, fatty liver, and multiple organ fibrosis. Arachidonic acid is the most abundant omega-6 polyunsaturated fatty acid (PUFA) and shares the same set of enzymes with omega-3 PUFAs, such as docosahexaenoic acid and eicosapentaenoic acid. The omega-3 PUFAs and metabolites, such as regioisomeric epoxyeicosatetraenoic acids and epoxydocosapentaenoic acids, have been reported to have strong vasodilatory and anti-inflammatory effects. Therefore, sEH may be a potential therapeutic target for metabolic disorders. In this review, we focus on our and other recent studies of the functions of sEH, including the effects of its eicosanoid products from both omega-3 and omega-6 PUFAs, in various metabolic diseases. We also discuss the possible cellular and molecular mechanisms underlying the regulation of sEH.

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“…Podocytes can also undergo EMT under conditions of high glucose (19), which is associated with increased podocyte detachment, microalbuminuria and more severe glomerular pathology. Several intracellular signaling pathways regulate EMT, including transforming growth factor-β/small mothers against decapentaplegic, Wnt/β-catenin and integrin-linked kinase (ILK) (20). Glycogen synthase kinase 3β (GSK-3β) is involved in all these pathways, and thus may be pivotal in podocyte EMT (20).…”

Section: Introductionmentioning

confidence: 99%

“…Several intracellular signaling pathways regulate EMT, including transforming growth factor-β/small mothers against decapentaplegic, Wnt/β-catenin and integrin-linked kinase (ILK) (20). Glycogen synthase kinase 3β (GSK-3β) is involved in all these pathways, and thus may be pivotal in podocyte EMT (20). Therefore, GSK-3β inhibitors have been investigated in mesangial proliferative glomerulonephritis, crescent glomerulonephritis and lupus nephritis (21).…”

Section: Introductionmentioning

confidence: 99%

GSK-3β inhibitor attenuates urinary albumin excretion in type 2 diabetic db/db mice, and delays epithelial-to-mesenchymal transition in mouse kidneys and podocytes

Wan

Liu

et al. 2016

Molecular Medicine Reports

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Abstract. The mechanism underlying epithelial-tomesenchymal transition (EMT) caused by high glucose (HG) stimulation in diabetic nephropathy (DN) remains to be fully elucidated. The present study investigated the effects of HG on EMT and the activity of glycogen synthase kinase 3β (GSK-3β) in podocytes and the kidneys of db/db mice, and assessed the effects of (2'Z, 3'E)-6-bromoindirubin-3'-oxime (BIO), an inhibitor of GSK-3β, on EMT and glomerular injury. The resulting data showed that the activity of GSK-3β was upregulated by HG and downregulated by BIO in the podocytes and the renal cortex. The expression levels of epithelial markers, including nephrin, podocin and synaptopodin, were decreased by HG and increased by BIO, whereas the reverse were true for mesenchymal markers, including α-smooth muscle actin (α-SMA) and fibronectin. The expression levels of β-catenin and Snail, in contrast to current understanding of the Wnt signaling pathway, were increased by HG and decreased by BIO. In addition, expression of the vitamin D receptor (VDR) was decreased by HG and increased by BIO. In conclusion, the present study revealed that the mechanism by which BIO inhibited HG-mediated EMT in podocytes and the renal cortex was primarily due to the VDR. Treatment with BIO protected renal function by maintaining the integrity of the filtration membrane and decreasing UAE, but not by regulating blood glucose. Therefore, GSK-3β may be used as a sensitive biomarker of DN, and its inhibition by BIO may be effective in the treatment of DN.

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Soluble epoxide hydrolase inhibition ameliorates proteinuria-induced epithelial-mesenchymal transition by regulating the PI3K-Akt-GSK-3β signaling pathway

Cited by 37 publications

References 27 publications

Lack of serum‐ and glucocorticoid‐inducible kinase 3 leads to podocyte dysfunction

Lack of serum‐ and glucocorticoid‐inducible kinase 3 leads to podocyte dysfunction

Soluble epoxide hydrolase: A potential target for metabolic diseases

GSK-3β inhibitor attenuates urinary albumin excretion in type 2 diabetic db/db mice, and delays epithelial-to-mesenchymal transition in mouse kidneys and podocytes

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