Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc

Yang, Shikun; Zhao, Li; Han, Yachun; Liu, Yu; Chen, Chao; Zhan, Ming; Xiong, Xiaofen; Zhu, Xuejing; Xiao, Li; Hu, Chun; Liu, Fuyou; Zhou, Zhiguang; Kanwar, Yashpal S.; Sun, Lin

doi:10.1016/j.redox.2017.07.002

Cited by 48 publications

(36 citation statements)

References 53 publications

(76 reference statements)

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“…Briefly, 4-μm-thick kidney tissue sections were prepared for hematoxylin-eosin (H&E), PAS and Masson trichrome staining, as described in ref [26] .…”

Section: Methodsmentioning

confidence: 99%

Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis

et al. 2018

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NLRP3/IL-1β activation via thioredoxin (TRX)/thioredoxin-interacting protein (TXNIP) following mitochondria ROS (mtROS) overproduction plays a key role in inflammation. However, the involvement of this process in tubular damage in the kidneys of patients with diabetic nephropathy (DN) is unclear. Here, we demonstrated that mtROS overproduction is accompanied by decreases in TRX expression and TXNIP up-regulation. In addition, we discovered that mtROS overproduction is also associated with increases in NLRP3/IL-1β and TGF-β expression in the kidneys of patients with DN and db/db mice. We reversed these changes in db/db mice by administering a peritoneal injection of MitoQ, an antioxidant targeting mtROS. Similar results were observed in human tubular HK-2 cells subjected to high-glucose (HG) conditions and treated with MitoQ. Treating HK-2 cells with MitoQ suppressed the dissociation of TRX from TXNIP and subsequently blocked the interaction between TXNIP and NLRP3, leading to the inhibition of NLRP3 inflammasome activation and IL-1β maturation. The effects of MitoQ were enhanced by pretreatment with TXNIP siRNA and abolished by pretreatment with monosodium urate (MSU) and TRX siRNA in vitro. These results suggest that mitochondrial ROS-TXNIP/NLRP3/IL-1β axis activation is responsible for tubular oxidative injury, which can be ameliorated by MitoQ via the inhibition of mtROS overproduction.

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“…Briefly, 4-μm-thick kidney tissue sections were prepared for hematoxylin-eosin (H&E), PAS and Masson trichrome staining, as described in ref [26] .…”

Section: Methodsmentioning

confidence: 99%

Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis

et al. 2018

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“…Then, the sections were stained in hematoxylin and eosin according to standard procedures. Collagen distribution in the aortic wall was evaluated by Masson staining [24] . Briefly, sections (8 µm) were dewaxed and rehydrated, followed by counterstaining with Weigert's iron hematoxylin (5–10 min), followed by Masson's trichrome staining solution.…”

Section: Methodsmentioning

confidence: 99%

Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress

Tong

et al. 2018

Redox Biology

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Neointimal hyperplasia as a consequence of vascular injury is aggravated by inflammatory reaction and oxidative stress. The α7 nicotinic acetylcholine receptor (α7nAChR) is a orchestrator of cholinergic anti-inflammatory pathway (CAP), which refers to a physiological neuro-immune mechanism that restricts inflammation. Here, we investigated the potential role of CAP in neointimal hyperplasia using α7nAChR knockout (KO) mice. Male α7nAChR-KO mice and their wild-type control mice (WT) were subjected to wire injury in left common carotid artery. At 4 weeks post injury, the injured aortae were isolated for examination. The neointimal hyperplasia after wire injury was significantly aggravated in α7nAChR-KO mice compared with WT mice. The α7nAChR-KO mice had increased collagen contents and vascular smooth muscle cells (VSMCs) amount. Moreover, the inflammation was significantly enhanced in the neointima of α7nAChR-KO mice relative to WT mice, evidenced by the increased expression of tumor necrosis factor-α/interleukin-1β, and macrophage infiltration. Meanwhile, the chemokines chemokine (C-C motif) ligand 2 and chemokine (CXC motif) ligand 2 expression was also augmented in the neointima of α7nAChR-KO mice compared with WT mice. Additionally, the depletion of superoxide dismutase (SOD) and reduced glutathione (GSH), and the upregulation of 3-nitrotyrosine, malondialdehyde and myeloperoxidase were more pronounced in neointima of α7nAChR-KO mice compared with WT mice. Accordingly, the protein expression of NADPH oxidase 1 (Nox1), Nox2 and Nox4, was also higher in neointima of α7nAChR-KO mice compared with WT mice. Finally, pharmacologically activation of CAP with a selective α7nAChR agonist PNU-282987, significantly reduced neointima formation, arterial inflammation and oxidative stress after vascular injury in C57BL/6 mice. In conclusion, our results demonstrate that α7nAChR-mediated CAP is a neuro-physiological mechanism that inhibits neointima formation after vascular injury via suppressing arterial inflammation and oxidative stress. Further, these results imply that targeting α7nAChR may be a promising interventional strategy for in-stent stenosis.

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“…Diabetic nephropathy (DN) is a most frequent microvascular complication of the diabetes mellitus (DM) with a high mortality. [1][2][3] The DN has been reported to be caused by many factors, such as genetic factors and activation of the polyol pathway; however, its pathogenesis is still not clear. [4][5][6] Fully understanding the pathogenesis of DN could help to find out its effective treatment.…”

Section: Introductionmentioning

confidence: 99%

LncRNA MALAT1 promoted high glucose‐induced pyroptosis of renal tubular epithelial cell by sponging miR‐30c targeting for NLRP3

Liu

Zhuo

et al. 2020

The Kaohsiung J of Med Scie

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Diabetic nephropathy (DN), characterized by the chronic loss of kidney function during diabetes, is a long‐term kidney disease that affects millions of populations. However, the etiology of DN remains unclear. DN cell model was established by treating HK‐2 cells with high glucose (HG) in vitro. Expression of metastasis‐associated lung adenocarcinoma transcript‐1 (MALAT1), miR‐30c, nucleotide binding and oligomerization domain‐like receptor protein 3 (NLRP3), caspase‐1, IL‐1β, and IL‐18 in treated HK‐2 cells were tested by quantitative polymerase chain reaction. HK‐2 cell pyroptosis was assessed using flow cytometry analysis. Lactate dehydrogenase (LDH) activity was examined with a LDH assay kit. Correlation among MALAT1, miR‐30c, and NLRP3 was examined via dual‐luciferase reporter assay. Here, we revealed that MALAT1 was upregulated, but miR‐30c was downregulated in HG‐treated HK‐2 cells, leading to upregulation of NLRP3 expression and cell pyroptosis. Knockdown of MALAT1 or overexpression of miR‐30c protected HK‐2 cells from HG‐induced pyroptosis. Meanwhile, we found that MALAT1 promoted NLRP3 expression by sponging miR‐30c through dual‐luciferase reporter assay. Moreover, the co‐transfection of sh‐MALAT1 and miR‐30c inhibitor could reverse the protective effects of the sh‐MALAT1 on the HG‐induced pyroptosis. These results confirmed that MALAT1 regulated HK‐2 cell pyroptosis by inhibiting miR‐30c targeting for NLRP3, contributing to a better understanding of DN pathogenesis and help to find out the effective treatment for DN.

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Probucol ameliorates renal injury in diabetic nephropathy by inhibiting the expression of the redox enzyme p66Shc

Cited by 48 publications

References 53 publications

Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis

Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis

Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress

LncRNA MALAT1 promoted high glucose‐induced pyroptosis of renal tubular epithelial cell by sponging miR‐30c targeting for NLRP3

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