Prolyl hydroxylase 2 (PHD2) inhibition protects human renal epithelial cells and mice kidney from hypoxia injury

Fang, Yi; Zhang, Hui; Zhong, Yun‐Shi; Ding, Xiaoqiang

doi:10.18632/oncotarget.11104

Cited by 22 publications

(15 citation statements)

References 35 publications

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“…These results may imply that PGE1 may have a protective effect on diabetic proximal tubules injury through inhibiting excessive autophagy. Our results are similar with some previous studies that inhibition of autophagy increased cell viability in proximal tubule cells exposed in CoCl 2 , PA or high glucose 16 , 33 , 34 . Thus, the advantages of targeting autophagy for the treatment of DN is recommended in new drug research.…”

Section: Discussionsupporting

confidence: 93%

Inhibition of insulin resistance by PGE1 via autophagy-dependent FGF21 pathway in diabetic nephropathy

Wei

Jin

et al. 2018

Sci Rep

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Insulin resistance is a critical process in the initiation and progression of diabetic nephropathy (DN). Alprostadil (Prostaglandin E1, PGE1) had protective effects on renal function. However, it is unknown whether PGE1 inhibited insulin resistance in renal tubule epithelial cells via autophagy, which plays a protective role in DN against insulin resistance. Insulin resistance was induced by palmitic acid (PA) in human HK-2 cells, shown as the decrease of insulin-stimulated AKT phosphorylation, glucose transporter-4 (GLUT4), glucose uptake and enhanced phosphorylation of insulin receptor substrate 1(IRS-1) at site serine 307 (pIRS-1ser307) and downregulated expression of IRS-1. Along with less abundance of p62, autophagy markers LC3B and Beclin-1 significantly increased in HK-2 cells exposed to PA. Such abnormal changes were significantly reversed by PGE1, which mimicked the role of autophagy gene 7 small interfering RNA (ATG7 siRNA). Furthermore, PGE1 promoted the protein expression of autophagy-related fibroblast growth factor-21 (FGF21), which alleviated insulin resistance. Results from western blotting and immunohistochemistry indicated that PGE1 remarkably restored autophagy, insulin resistance and the FGF21 expression in rat kidney of type 2 diabetes mellitus (T2DM). Collectively, we demonstrated the potential protection of PGE1 on insulin resistance in renal tubules via autophagy-dependent FGF21 pathway in preventing the progression of DN.

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Section: Discussionsupporting

confidence: 93%

Inhibition of insulin resistance by PGE1 via autophagy-dependent FGF21 pathway in diabetic nephropathy

Wei

Jin

et al. 2018

Sci Rep

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“…In addition, whereas HIF-1α was inducible in physiological renal mouse, rat and human tubular epithelia, HIF-2α was never detected in these cells in any species, and tubular cells required VHL inactivation to allow HIF-2α expression 12 . Recently, however, cobalt chloride treatment increased HIF-2α as well as HIF-1α protein expression in HK-2 cells, and renal HIF-1α and HIF-2α protein expression was simultaneously upregulated with L-mimosine administration after ischemia-reperfusion injury 18 . If HIF-1α and HIF-2α expressions are induced in human renal tubular cells by non-specific HIF stabilizers, the results of this study may have the clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis

Kong

Lim

et al. 2017

Sci Rep

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Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2α at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF-2α activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1α activation. In conclusion, late-stage renal tubular HIF-2α activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD.Regardless of the type of initial injury to the kidney, renal hypoxia is the common final pathway of renal fibrosis 1 , which is regarded a prime target for preventing the progression of chronic kidney disease (CKD) to end-stage renal disease.Hypoxia-inducible factor (HIF) is a key transcriptional factor in the regulation of the adaptive response to hypoxia. HIF is a heterodimeric complex that has three forms (HIF-1, HIF-2, and HIF-3), which differ in their α-subunit. If the α-subunit is not hydroxylated by prolyl hydroxylase under hypoxic conditions, it cannot be recognized by von Hippel-Lindau tumor suppressor protein (pVHL), which is part of an E3-ubiquitin ligase complex that targets HIF-α for proteosomal degradation 2 . Then, α-subunit combines with a constitutively expressed β-subunit in the nucleus. Finally, HIF regulates the expression of salient target genes that are involved in numerous biological processes, including energy metabolism, angiogenesis, erythropoiesis, iron metabolism, cell proliferation, and apoptosis 2 . HIF activation ameliorates tissue hypoxia and eventually helps the hypoxic cells survive. Even though the effect of HIF activation in CKD has been widely evaluated, the results have been inconsistent. Reduced renal fibrosis by genetic ablation of tubular HIF-1 suggested a profibrotic role of HIF 3 , while contrary results demonstrated that an HIF stabilizer exerted a beneficial effect on renal fibrosis in an animal model of CKD 4 . Accumulating evidence suggests that HIFs exert beneficial effects in diabetic nephropathy. Activation of HIFs by cobalt chloride, a non-specific pan-HIF activator, attenuated diabetes-induced alteration in oxygen m...

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“…The empty construct pcDNA3.1 was transfected as a control (pc-NC). siRNA sequences against Hsp27 and a scrambled control siRNA (RiboBio, Guangzhou, China) were transfected into cells as si-Hsp27 and si-NC group [19]. All transfection were performed using Lipofectamine 3000 reagent (Invitrogen, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

Cytoprotective Effect of Heat Shock Protein 27 Against Lipopolysaccharide-Induced Apoptosis of Renal Epithelial HK-2 Cells

Li¹,

Li³

et al. 2017

Cell Physiol Biochem

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Background:In response to various stimuli, heat shock protein 27 (Hsp27) functions as an anti-apoptotic or/and anti-inflammatory factor which confers a survival advantage to cells. This study was aimed to explore whether Hsp27 also has a cytoprotective role in human renal tubular epithelial cells, and to evaluate its potential in treating septic acute kidney injury (septic AKI). Methods: HK-2 cells were subjected to different concentrations (0-10 μg/mL) of lipopolysaccharide (LPS) for various times (0-24 h) to establish a septic AKI model in vitro. Before LPS administration, HK-2 cells were transfected either with vectors or siRNA against Hsp27, and the changes in cell viability and apoptotic cells rate were assessed using CCK-8 and flow cytometry. The expression changes in apoptosis-related proteins, proinflammatory cytokines and chemokine, as well as main factors in NF-κB and JNK pathways were mainly determined by Western blotting. Besides, the relationship between Hsp27 and Bcl-2 was detected by co-immunoprecipitation. Results: LPS remarkably damaged HK-2 cells by reduction of cell viability, induction of apoptosis, and stimulation of proinflammatory cytokines and chemokine release. Hsp27 overexpression significantly impaired LPS-induced damage in HK-2 cells. Hsp27 overexpression couldn't alter the mRNA level of Bcl-2, but could interact with Bcl-2 at an endogenous level. Both NF-κB and JNK pathways were activated by LPS, while were blocked in Hsp27-overexpressing cells. Conclusion: Hsp27 overexpression conferred a survival advantage to LPS-injured HK-2 cells by controlling cell viability, apoptosis and inflammation, possibly via interaction with Bcl-2 and modulation of NF-κB and JNK pathways.

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Prolyl hydroxylase 2 (PHD2) inhibition protects human renal epithelial cells and mice kidney from hypoxia injury

Cited by 22 publications

References 35 publications

Inhibition of insulin resistance by PGE1 via autophagy-dependent FGF21 pathway in diabetic nephropathy

Inhibition of insulin resistance by PGE1 via autophagy-dependent FGF21 pathway in diabetic nephropathy

Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis

Cytoprotective Effect of Heat Shock Protein 27 Against Lipopolysaccharide-Induced Apoptosis of Renal Epithelial HK-2 Cells

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