Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis

Cheng, Rui; Ding, Lexi; He, Xianghui; Takahashi, Yusuke; Xing, Jian

doi:10.2337/db16-0426

Cited by 58 publications

(39 citation statements)

References 49 publications

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“…FA, a PPARα agonist, has shown antiangiogenic effects in PDR patients and in several NV animal models including VKO mice . Our previous study reported that FA inhibited the Wnt signaling pathway . The present study indicated that FA significantly decreased mitochondrial biogenesis and ROS production in isolated EPCs in vitro (Figs.…”

Section: Discussionsupporting

confidence: 64%

“…Dysregulation of Wnt signaling is an important cause of impaired mitochondrial biogenesis and reactive oxygen species (ROS) generation, leading to exacerbated pathologic outcomes in tumor development and abnormal NV . Several studies have reported that the Wnt signaling pathway regulates NV in the development of ocular diseases . In 2013, our group reported that the aberrant activation of the Wnt pathway played an important role in hypoxia‐induced EPC release using the oxygen‐induced retinopathy mouse model .…”

Section: Introductionmentioning

confidence: 99%

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Canonical Wnt Signaling Promotes Neovascularization Through Determination of Endothelial Progenitor Cell Fate via Metabolic Profile Regulation

et al. 2019

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Endothelial progenitor cells (EPCs) contribute to blood vessel formation. Canonical Wnt signaling plays an important role in physiological and pathological angiogenesis and EPC fate regulation. However, the mechanism for Wnt signaling to regulate EPC fate in neovascularization (NV) has not been clearly defined. Here, we showed that very low‐density lipoprotein receptor knockout (Vldlr −/−) mice, a model of ocular NV induced by Wnt signaling overactivation, have increased EPC numbers in the bone marrow, blood, and retina, as well as an elevated mitochondrial membrane potential indicating higher mitochondrial function of EPCs in the circulation. Isolated EPCs from Vldlr −/− mice showed overactivated Wnt signaling, correlating with increased mitochondrial function, mass, and DNA copy numbers, compared with WT EPCs. Our results also demonstrated that Wnt signaling upregulated mitochondrial biogenesis and function, while inhibiting glycolysis in EPCs, which further decreased EPC stemness and promoted EPCs to a more active state toward differentiation, which may contribute to pathologic vascular formation. Fenofibric acid, an active metabolite of fenofibrate, inhibited Wnt signaling and mitochondrial function in EPCs and decreased EPC numbers in Vldlr −/−mice. It also decreased mitochondrial biogenesis and reactive oxygen species production in Vldlr −/− EPCs, which may be responsible for its therapeutic effect on diabetic retinopathy. These findings demonstrated that Wnt signaling regulates EPC fate through metabolism, suggesting potential application of the EPC metabolic profile as predictor and therapeutic target for neovascular diseases. stem cells 2019;37:1331–1343

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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Canonical Wnt Signaling Promotes Neovascularization Through Determination of Endothelial Progenitor Cell Fate via Metabolic Profile Regulation

et al. 2019

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“…Cells from a human renal tubular epithelial cell line (HK‐2) were purchased from the ATCC and cultured with DMEM containing 10% foetal bovine serum (Gibco, Life Technologies). Cells were infected with lentivirus particles harbouring CCNG2 or control GFP lentivirus (GeneChem) and divided into high‐glucose (HG; 30 mmol/L d ‐glucose) and low‐glucose (LG; 5.5 mmol/L d ‐glucose and 24.5 mmol/L l ‐glucose) treatment groups (Figure ) . Cells were starved by incubation in DMEM containing 1% serum for 24 hours, and then, the media was replaced with DMEM containing 10% serum and the indicated concentrations of glucose.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were infected with lentivirus particles harbouring CCNG2 or control GFP lentivirus (GeneChem) and divided into high-glucose (HG; 30 mmol/L d-glucose) and low-glucose (LG; 5.5 mmol/L d-glucose and 24.5 mmol/L l-glucose) treatment groups ( Figure S2). 37,38 Cells were starved by incubation in DMEM containing 1% serum for 24 hours, and then, the media was replaced with DMEM containing 10% serum and the indicated concentrations of glucose. Cells were infected with lentivirus particles harbouring CCNG2 and exposed to the Wnt signalling activator CHIR99021 (1 mmol/L; R&D Systems; 4423) or an equivalent volume of DMSO in DMEM (negative control) for 72 hours.…”

Section: Cell Culture Transfection and Treatmentmentioning

confidence: 99%

Cyclin G2 regulates canonical Wnt signalling via interaction with Dapper1 to attenuate tubulointerstitial fibrosis in diabetic nephropathy

Zhao

Gao

et al. 2020

J Cellular Molecular Medi

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Cyclin G2 (CCNG2) is an atypical cyclin that inhibits cell cycle progression and is often dysregulated in human cancers. Cyclin G2 in the occurrence and development of diabetic nephropathy (DN), one of the most severe diabetic complications, has not been fully identified. In this study, we investigated the function and regulatory mechanism of cyclin G2 in DN. In vivo studies revealed that a deficiency of cyclin G2 significantly increased albuminuria and promoted tubulointerstitial fibrosis in established DN. Cyclin G2 regulated the expression of fibrosis‐related proteins via the canonical Wnt signalling pathway in renal tubular epithelial cells. Moreover, the binding of cyclin G2 to Dapper1 (Dpr1/DACT1), a protein involved in Wnt signalling, decreased the phosphorylation of Dpr1 at Ser762 by casein kinase 1 (CK1) and suppressed the Wnt signalling pathway. These findings reveal that cyclin G2 can protect against renal injury and fibrosis associated with DN and, thus, is a new target for the prevention and treatment of diabetic complications.

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“…However, previous studies have shown that the protective effect of FF against DN can be independent of its lipid-lowering effect [11,12] . FF also has renal protective effects in a model of type 1 diabetes (T1D), which are achieved through activation of the transforming growth factor (TGF)-β1/smad3 and canonical Wnt pathways that ameliorate renal fibrosis [13,14] . However, the underlying mechanisms of the renal protective effects of FF in T1D have not been fully investigated.…”

Section: Ivyspringmentioning

confidence: 99%

The Role of Akt2 in the Protective Effect of Fenofibrate against Diabetic Nephropathy

Cheng¹,

Zhang²,

Ma³

et al. 2020

Int. J. Biol. Sci.

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Fenofibrate (FF) protects against diabetic nephropathy (DN) in type 1 diabetic (T1D) mice by upregulating the expression of fibroblast growth factor 21 (FGF21), leading to the activation of the Akt-mediated Nrf2 antioxidant pathways. Here, we examined which isoforms of Akt contribute to FF activation of FGF21-mediated renal protection by examining the phosphorylation and expression of three isoforms, Akt1, Akt2, and Akt3. T1D induced by a single intraperitoneal dose of streptozotocin (STZ) resulted in reduced phosphorylation of one isoform, Akt2, but FF treatment increased renal Akt2 phosphorylation in these and normal mice, suggesting a potential and specific role for renal Akt2 in FF protection against T1D. This was further confirmed using in vitro cultured HK-2 human kidney tubule cells exposed to high glucose (HG) with siRNA silencing of the Akt2 gene and STZ-induced diabetic Akt2-knockout mice with and without 3-month FF treatment. In normal HK-2 cells exposed to HG for 24 hours, FF completely prevented cell death, reduced total Akt expression and glycogen synthase kinase (GSK)-3β phosphorylation, increased nuclear accumulation of Fyn, and reduced nuclear Nrf2 levels. These positive effects of FF were partially abolished by silencing Akt2 expression. Similarly, FF abolished T1D-induced renal oxidative stress, inflammation, and renal dysfunction in wild-type mice, but was only partially effective in Akt2-KO mice. Furthermore, FF treatment stimulated phosphorylation of AMPKα, an important lipid metabolism mediator, which in parallel with Akt2 plays an important role in FF protection against HG-induced HK-2 cells oxidative stress and damage. These results suggest that FF protects against DN through FGF21 to activate both Akt2/GSK-3β/Fyn/Nrf2 antioxidants and the AMPK pathway. Therefore, FF could be repurposed for the prevention of DN in T1D patients.Key words: diabetic nephropathy; Akt2, fibroblast growth factor 21; nuclear factor erythroid 2-related factor 2; peroxisome proliferator-activated receptor α agonist.

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Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis

Cited by 58 publications

References 49 publications

Canonical Wnt Signaling Promotes Neovascularization Through Determination of Endothelial Progenitor Cell Fate via Metabolic Profile Regulation

Canonical Wnt Signaling Promotes Neovascularization Through Determination of Endothelial Progenitor Cell Fate via Metabolic Profile Regulation

Cyclin G2 regulates canonical Wnt signalling via interaction with Dapper1 to attenuate tubulointerstitial fibrosis in diabetic nephropathy

The Role of Akt2 in the Protective Effect of Fenofibrate against Diabetic Nephropathy

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