Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy

Cheng, Yiyun; Zhang, Jingjing; Guo, Weiying; Li, Fengsheng; Sun, Weixia; Chen, Jing; Zhang, Chi; Lu, Xuemian; Tan, Yi; Feng, Wenke; Fu, Yue; Liu, Gilbert C.; Xu, Zhenhe; Cai, Lu

doi:10.1016/j.freeradbiomed.2016.02.002

Cited by 88 publications

(77 citation statements)

References 51 publications

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“…The kidney has been identified as a target of FGF21, and exogenous administration of FGF21 protein has been shown to improve systemic metabolism and exert antifibrotic properties in kidneys of db/db mice (16). More recently, it has been demonstrated that upregulation of renal FGF21 expression in streptozotocin-treated C57/BL mice leads to a significant renal protection, believed to be due to PI3K/Akt/GSK3β/Fyn-mediated activation of the Nrf2 antioxidative pathway (32). In this study we identified significant upregulation of renal FGF21 mRNA in MR-fed females, in addition to increased expression of the FGF21 co-receptor, β-Klotho.…”

Section: Discussionsupporting

confidence: 55%

Methionine restriction improves renal insulin signalling in aged kidneys

Grant

Lees

Forney

et al. 2016

Mechanisms of Ageing and Development

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Dietary methionine restriction (MR) leads to loss of adiposity, improved insulin sensitivity and lifespan extension. The possibility that dietary MR can protect the kidney from age-associated deterioration has not been addressed. Aged (10-month old) male and female mice were placed on a MR (0.172% methionine) or control diet (0.86% methionine) for 8-weeks and blood glucose, renal insulin signalling, and gene expression were assessed. Methionine restriction lead to decreased blood glucose levels compared to control-fed mice, and enhanced insulin-stimulated phosphorylation of PKB/Akt and S6 in kidneys, indicative of improved glucose homeostasis. Increased expression of lipogenic genes and downregulation of PEPCK were observed, suggesting that kidneys from MR-fed animals are more insulin sensitive. Interestingly, renal gene expression of the mitochondrial uncoupling protein UCP1 was upregulated in MR-fed animals, as were the anti-ageing and renoprotective genes Sirt1, FGF21, klotho, and β-klotho. This was associated with alterations in renal histology trending towards reduced frequency of proximal tubule intersections containing vacuoles in mice that had been on dietary MR for 190 days compared to control-fed mice, which exhibited a pre-diabetic status. Our results indicate that dietary MR may offer potential in ameliorating the renal functional decline related to ageing and other disorders associated with metabolic dysfunction by enhancing renal insulin sensitivity and renoprotective gene expression.

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Section: Discussionsupporting

confidence: 55%

Methionine restriction improves renal insulin signalling in aged kidneys

Grant

Lees

Forney

et al. 2016

Mechanisms of Ageing and Development

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“…Nrf2 plays a critical role in the cellular response to oxidative stress 25, 26 . Because increased CXCR7 expression decreased both ox-LDL-and HG-induced oxidative stress, we tested whether CXCR7 upregulation activate Nrf2 and its downstream target genes.…”

Section: Resultsmentioning

confidence: 99%

“…Several recent studies showing that the Akt/GSK-3β/Fyn pathway plays a pivotal role in regulation of Nrf2 nuclear export and degradation 25, 29, 30, 45, 46 . Based on those studies and Akt phosphorylation results, we hypothesized that SDF-1/CXCR7 signaling activates Nrf2 via the Akt/GSK-3β/Fyn pathway.…”

Section: Discussionmentioning

confidence: 99%

Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia

Dai

Yan

Zeng

et al. 2017

Circulation Research

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Rationale Endothelial progenitor cells (EPCs) respond to SDF-1 through receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes induced EPCs dysfunction remains unknown. Objective To determine the role of SDF-1 receptors in diabetic EPCs dysfunction. Methods and Results CXCR7 expression, but not CXCR4 was reduced in EPCs from db/db mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, while up-regulation of CXCR7 rescued angiogenic function of EPCs from db/db mice. In normal EPCs treated with oxidized low-density lipoprotein (ox-LDL) or high glucose (HG) also reduced CXCR7 expression, impaired tube formation and increased oxidative stress and apoptosis. The damaging effects of ox-LDL or HG were markedly reduced by SDF-1 pretreatment in EPCs transduced with CXCR7 lentivirus (CXCR7-EPCs) but not in EPCs transduced with control lentivirus (Null-EPCs). Most importantly, CXCR7-EPCs were superior to Null-EPCs for therapy of ischemic limbs in db/db mice. Mechanistic studies demonstrated that ox-LDL or HG inhibited Akt and GSK-3β phosphorylation, nuclear export of Fyn and nuclear localization of Nrf2, blunting Nrf2 downstream target genes HO-1, NQO-1 and catalase, and inducing an increase in EPC oxidative stress. This destructive cascade was blocked by SDF-1 treatment in CXCR7-EPCs. Furthermore, inhibition of PI3K/Akt prevented SDF-1/CXCR7-mediated Nrf2 activation and blocked angiogenic repair. Moreover, Nrf2 knockdown almost completely abolished the protective effects of SDF-1/CXCR7 on EPC function in vitro and in vivo. Conclusions Elevated expression of CXCR7 enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by an Akt/GSK-3β/Fyn pathway via increased activity of Nrf2.

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“…FGF21 gene deletion further enhances the pathological damage while rFGF21 replenishment significantly prevents it [7, 8, 91]. Fenofibrate protects against type 1 DN by FGF21-mediated upregulation of the nuclear factor E2-related factor 2 (Nrf2) antioxidant pathway [92]. In cisplatin-induced acute kidney injury (AKI), silencing of FGF21 aggravated tubular cell injury, whereas supplementation of rFGF21 protected against cisplatin nephrotoxicity [7, 8, 93].…”

Section: Fgf21 In Preclinical Experimental Animal Studiesmentioning

confidence: 99%

Fibroblast growth factor 21 in chronic kidney disease

et al. 2018

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Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF family that acts as a metabolic regulator of both glucose and lipid metabolism. Similar to fibroblast growth factor 23 (FGF23), serum FGF21 levels rise progressively with the loss of renal function, reaching 20 times normal values in end-stage renal disease. In patients with chronic kidney disease (CKD), higher serum FGF21 levels correlate with poorer metabolic profile, higher inflammatory markers, more comorbidities, and higher mortality. The high serum FGF21 levels are above and beyond what can be explained by the loss of FGF21 renal clearance, suggesting increased production and/or impaired non-renal clearance. In diabetic nephropathy, serum FGF21 levels correlate with the severity of albuminuria and faster loss of glomerular filtrate rate and can potentially be a biomarker of poor prognostic. The observational and associative human data contrast sharply with in vitro and in vivo preclinical experimental data, which is more in line with a protective role of FGF21 in chronic nephropathies. We here review the physiology of FGF21, and the literature regarding its behavior in CKD with particular focus on diabetic nephropathy. Finally, we speculate on the role of FGF21 in CKD.

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Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy

Cited by 88 publications

References 51 publications

Methionine restriction improves renal insulin signalling in aged kidneys

Methionine restriction improves renal insulin signalling in aged kidneys

Elevating CXCR7 Improves Angiogenic Function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 Activation in Diabetic Limb Ischemia

Fibroblast growth factor 21 in chronic kidney disease

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