Role of Protein Kinase G and Reactive Oxygen Species in the Regulation of Podocyte Function in Health and Disease

Piwkowska, Agnieszka

doi:10.1002/jcp.25613

Cited by 16 publications

(8 citation statements)

References 78 publications

(117 reference statements)

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“…Podocytes form an important cellular layer of the glomerular filtration barrier, which is involved in the regulation of glomerular permselectivity [34]. Podocyte injury or dysfunction plays a pivotal role in the development of proteinuria in all forms of glomerular nephritis and DN [35, 36]. Hence, maintaining the structural and functional integrity of podocytes and protecting podocytes from injury have become potential therapeutic approaches for CKD.…”

Section: Discussionmentioning

confidence: 99%

Palmitic Acid-Induced Podocyte Apoptosis via the Reactive Oxygen Species-Dependent Mitochondrial Pathway

Liu

Chen

Sun

et al. 2018

Kidney Blood Press Res

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Background/Aims: Chronic kidney disease (CKD) is often accompanied by hyperlipidemia, which accelerates progression of the disease. Podocyte injury can lead to dysfunction of the glomerular filtration barrier, which is associated with proteinuria, a risk marker for the progression of CKD. Our previous studies demonstrated that palmitic acid (PA) can induce podocyte apoptosis; however, the underlying mechanisms are unclear. In the present study, we investigated the specific molecular mechanisms of PA-induced apoptosis in cultured podocytes. Methods: We cultured mouse podocytes and treated them with PA. Then, cell viability was measured using the Cell Counting Kit-8 colorimetric assay, lipid uptake was assessed by Oil Red O staining and boron-dipyrromethene staining, apoptosis was measured by flow cytometry, mitochondrial injury was assessed by JC-1 staining and transmission electron microscopy, and mitochondrial production of reactive oxygen species (ROS) was evaluated by fluorescence microscopy using the MitoSOX Red reagent. The effects of PA on the mitochondria-mediated caspase activation pathway were investigated by examining the expression of caspase-8, cleaved caspase-9, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2), Bax, Bid, cytochrome c, and Fas-associated protein with death domain (FADD) using western blotting. The translocation of Bax and cytochrome c were detected by immunofluorescence. Results: PA treatment significantly increased lipid accumulation and induced podocyte apoptosis. We investigated whether the two primary apoptosis signaling pathways (death receptor-mediated pathway and mitochondria-mediated pathway) were involved in the execution of PA-induced podocyte apoptosis, and found that the levels of FADD, caspase-8, and Bid did not significantly change during this process. Meanwhile, PA treatment induced an increase in Bax protein expression and a decrease in Bcl-2 protein expression, with Bax translocation to the mitochondria. Furthermore, PA treatment induced mitochondrial impairment, and triggered the release of cytochrome c from the mitochondria to cytosol, with a concomitant dose-dependent increase in the levels of cleaved caspase-9, cleaved caspase-3, and PARP. Meanwhile, PA treatment increased mitochondrial production of ROS, and the mitochondria-targeted antioxidant mitoTEMPO significantly ameliorated PA-induced podocyte apoptosis. Conclusion: Our findings indicated that PA induced caspase-dependent podocyte apoptosis through the mitochondrial pathway, and mitochondrial ROS production participated in this process, thus potentially contributing to podocyte injury

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Section: Discussionmentioning

confidence: 99%

Palmitic Acid-Induced Podocyte Apoptosis via the Reactive Oxygen Species-Dependent Mitochondrial Pathway

Liu

Chen

Sun

et al. 2018

Kidney Blood Press Res

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show abstract

“…13 Podocytes are especially vulnerable to oxidative stress, which often leads to their dysfunction and causes proteinuria. 14,15 For instance, knockout mice lacking extracellular superoxide dismutase, an antioxidant expressed at high levels in normal adult kidneys, are sensitized to various glomerular injury induced by doxorubicin, chronic angiotensin II infusion, or protein overload and experience more severe proteinuria compared with wild-type control subjects. 16 However, extracellular superoxide dismutase null mice exhibit no difference with wild-type control subjects in kidney injury after unilateral ureteral obstruction.…”

mentioning

confidence: 99%

Wnt/β-catenin links oxidative stress to podocyte injury and proteinuria

Zhou

Chen

et al. 2019

Kidney International

116

108

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Podocyte injury is the major cause of proteinuria in primary glomerular diseases. Oxidative stress has long been thought to play a role in triggering podocyte damage; however, the underlying mechanism remains poorly understood. Here we show that the Wnt/b-catenin pathway is involved in mediating oxidative stress-induced podocyte dysfunction. Advanced oxidation protein products, a marker and trigger of oxidative stress, were increased in the serum of patients with chronic kidney disease and correlated with impaired glomerular filtration, proteinuria, and circulating level of Wnt1. Both serum from patients with chronic kidney disease and exogenous advanced oxidation protein products induced Wnt1 and Wnt7a expression, activated b-catenin, and reduced expression of podocyte-specific markers in vitro and in vivo. Blockade of Wnt signaling by Klotho or knockdown of b-catenin by shRNA in podocytes abolished b-catenin activation and the upregulation of fibronectin, desmin, matrix metalloproteinase-9, and Snail1 triggered by advanced oxidation protein products. Furthermore, conditional knockout mice with podocyte-specific ablation of b-catenin were protected against podocyte injury and albuminuria after treatment with advanced oxidation protein products. The action of Wnt/b-catenin was dependent on the receptor of advanced glycation end products (RAGE)mediated NADPH oxidase induction, reactive oxygen species generation, and nuclear factor-kB activation. These studies uncover a novel mechanistic linkage of oxidative stress, Wnt/b-catenin activation, and podocyte dysfunction.

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“…Previous studies have reported that ROS may be upstream signals for activation of p38 MAPK [30][31][32]. Interestingly, ROS produced by NADPH oxidase may be fed back to the G protein itself, since ROS directly activate Gi and Go without activating receptors [25,33]. ROS leads to an increase in the binding form of Gαi-GTP, resulting in the release of Gβγ from Gi and Go, which can activate the phosphorylated P38 MAPK and phosphoinositol 3-OH kinase signaling pathway, leading to Akt dephosphoryla-tion [33].…”

Section: Discussionmentioning

confidence: 99%

Tanshinone IIA Inhibits Tissue Factor Expression Induced by Thrombin in Human Umbilical Vein Endothelial Cells via PAR-1 and p38 MAPK Signaling Pathway

Zhang

et al. 2022

Acta Haematol

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Background: The potential signaling pathway of TSA suppressing TF expression induced by thrombin was unknown. Thus, the transcription of TF in HUVECs and the expressions of DCF, phospho-p38 MAPK, NADPH oxidase 4, PAR-1, and NF-κB were detected in our study. Methods: HUVECs were randomly divided into control group, thrombin-treated group (with 5 U/mL of thrombin), and 4 TSA-treated groups (with 5 U/mL of thrombin plus TSA with 4 different concentrations of 1 μg/mL, 10 μg/mL, 100 μg/mL, and 1 mg/mL, respectively). Results: After incubation with thrombin for 6 h at 37°C, the results showed increased TF mRNA, TF procoagulant activity, and antigen of TF in HUVECs of thrombin-treated group (p < 0.01); however, they were restored by TSA in a dose-dependent manner (p < 0.01). In addition, reactive oxygen species (ROS), phospho-p38 MAPK, NADPH oxidase 4, NF-κB, and PAR-1 expressed more intensively, and phosphorylated Akt decreased obviously in HUVECs after thrombin stimulation (p < 0.01); however, they were reversed to different extents by TSA in a dose-dependent manner (p < 0.01). Conclusions: Study suggests that TSA inhibits TF expression induced by thrombin in cultured HUVECs, and the potential signaling pathway of which is TSA interrupts the activation of PAR-1 and NADPH oxidase as well as derivative ROS generation, thereafter suppresses the activation of NF-κB, the upstream signal molecule of TF, via hampering phosphorylation of p38 MAPK and dephosphorylation of Akt, and finally inhibits thrombin-induced TF overexpression.

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Role of Protein Kinase G and Reactive Oxygen Species in the Regulation of Podocyte Function in Health and Disease

Cited by 16 publications

References 78 publications

Palmitic Acid-Induced Podocyte Apoptosis via the Reactive Oxygen Species-Dependent Mitochondrial Pathway

Palmitic Acid-Induced Podocyte Apoptosis via the Reactive Oxygen Species-Dependent Mitochondrial Pathway

Wnt/β-catenin links oxidative stress to podocyte injury and proteinuria

Tanshinone IIA Inhibits Tissue Factor Expression Induced by Thrombin in Human Umbilical Vein Endothelial Cells via PAR-1 and p38 MAPK Signaling Pathway

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