Gasdermin D Protects Mouse Podocytes Against High-Glucose-Induced Inflammation and Apoptosis via the C-Jun N-Terminal Kinase (JNK) Pathway

Li, Huifang; Zhao, Kunxiao; Li, Ying

doi:10.12659/msm.928411

Cited by 10 publications

(9 citation statements)

References 13 publications

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“…The JNK pathway is an important regulatory pathway in apoptosis ( 27 ). Our results showed that Cdc42 induced the apoptosis of MPC5 cells partly through the JNK pathway, which is consistent with a previous study that demonstrated that gasdermin D knockdown attenuated HG-induced apoptosis by inhibiting the phosphorylation of JNK ( 26 ).…”

Section: Discussionsupporting

confidence: 93%

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Cdc42 upregulation under high glucose induces podocyte apoptosis and impairs β-cell insulin secretion

Jiang

Shuai

et al. 2022

Front. Endocrinol.

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ObjectivesThe progressive impairment of β-cell function results in prolonged deterioration in patients with type 2 diabetes mellitus (T2DM). Interestingly, the finding on pancreatitis secondary to renal injury suggests that potential communication exists between kidney and pancreas. Therefore, we aimed to investigate cell division cycle 42 (Cdc42)-mediated podocyte apoptosis and its effect on insulin secretion in islet β-cells.MethodsType 2 diabetic nephropathy mouse models were established to identify the expression of Cdc42 in podocytes by immunohistochemistry. An in vitro co-culture of mouse podocyte MPC5 and β-TC6 cells was preliminarily established. Subsequently, podocyte apoptosis induced by high glucose and Cdc42 was detected by TUNEL staining and western blotting. In addition, the JNK pathway was examined to determine the mechanism of apoptosis in MPC5 cells. Finally, insulin secretion and expression in β-TC6 cells as well as malondialdehyde (MDA) and superoxide dismutase (SOD) levels in both cell types were examined after the regulation of Cdc42 in MPC5 cells.ResultsCdc42 was highly expressed in the podocytes of diabetic nephropathy mice. Exposure to 25 mM glucose for 48 h induced a significant upregulation of Cdc42, Bax, and cleaved caspase-3 as well as a decreased Bcl-2 expression. In addition, marked apoptosis of MPC5 cells was observed compared to normal glucose treatment. After transfection with Cdc42 plasmid, apoptosis of MPC5 cells was enhanced with an increased expression of p-JNK, whereas inhibition of Cdc42 significantly alleviated podocyte apoptosis accompanied by a downregulation of p-JNK. The glucose-stimulated insulin secretion level of β-TC6 cells decreased after the upregulation of Cdc42 in MPC5 cells. Immunofluorescence staining for insulin showed that co-culture with MPC5 cells carrying the Cdc42 plasmid significantly reduced insulin expression, whereas inhibition of Cdc42 in MPC5 cells alleviated the above-mentioned abnormality of β-TC6 cells. The expression of Cdc42 and p-p38 in β-TC6 cells increased following the upregulation of Cdc42 in MPC5 cells; this was concurrent with augmented MDA levels and decreased SOD activity. The opposite result was observed for Cdc42 knockdown in MPC5 cells.ConclusionsCdc42 in podocytes plays a crucial role in insulin secretion by β-cells, which may provide a new therapeutic target to prevent the vicious cycle of β-cell dysfunction in T2DM.

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Section: Discussionsupporting

confidence: 93%

“…JNK is a member of the mitogen-activated protein kinase superfamily, which can be activated by phosphorylation of the N-terminal Ser-63 and Ser-73 residues ( 25 , 26 ). The JNK pathway is an important regulatory pathway in apoptosis ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Cdc42 upregulation under high glucose induces podocyte apoptosis and impairs β-cell insulin secretion

Jiang

Shuai

et al. 2022

Front. Endocrinol.

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“…Disulfiram and NSA can directly affect GSDMD pore formation to inhibit pyroptosis [ 35 , 36 ]. In addition, GSDMD knockdown can attenuate high-glucose-induced inflammation and apoptosis in podocytes [ 37 ]. GSDME knockdown attenuated ATP-induced cell death and HMGB1 release in RAW264.7 cells [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells

et al. 2022

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Histone deacetylase 11 (HDAC11), a sole member of the class IV HDAC subfamily, participates in various cardiovascular diseases. Recent evidence showed that pyroptosis was a form of inflammatory programmed cell death and is critical for atherosclerosis (AS). However, little is known about the effect of HDAC11 on endothelial cell pyroptosis in AS. Thus, this study aims to investigate the role of HDAC11 in vascular endothelial cell pyroptosis and its molecular mechanism. Firstly, we found that HDAC11 expression was up-regulated and pyroptosis occurred in the aorta of ApoE−/− mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found the treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α) resulted in pyroptosis, as evidenced by activation of caspase-1 and caspase-3 activation, cleavage of downstream gasdermin D (GSDMD) and gasdermin E (GSDME/DFNA5), the release of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-18, as well as elevation of LDH activity and increase of propidium iodide (PI)-positive cells. Besides, TNF-α increased HDAC11 expression and induced pyroptosis via TNFR1 in HUVECs. HDAC11 knockdown mitigated pyroptosis by suppressing both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways in TNF-α-induced HUVECs. Moreover, GSDME knockdown by siRNA significantly decreased pyroptosis and inflammatory response, while treatment with disulfiram or necrosulfonamide (NSA) further augmented the inhibitory effects of GSDME siRNA on pyroptosis and inflammatory response. Further studies found HDAC11 formed a complex with ERG and decreased the acetylation levels of ERG. More importantly, ERG knockdown augmented vascular endothelial cell pyroptosis in TNF-α-induced HUVECs. Taken together, our study suggests that HDAC11 might promote both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways leading to pyroptosis via regulation of ERG acetylation in HUVECs. Modulation of HDAC11 may serve as a potential target for therapeutic strategies of AS.

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“…When caspase-11 is overexpressed, caspase-3 can also be activated to promote apoptosis ( Miao et al, 2018 ). Notably, transfection of podocytes with GSDMD siRNA reversed HG-induced inflammation and apoptosis, which may be related to the blocking of JNK signaling pathway ( Li et al, 2021a ). Although apoptosis-related proteins were also activated in caspase-3-dependent pyroptosis signaling pathway, pyroptosis activation occurred more rapidly ( Tsuchiya, 2021 ).…”

Section: Three Molecular Mechanisms Of Pyroptosismentioning

confidence: 99%

NLRP3-mediated pyroptosis in diabetic nephropathy

Wan

Pan

et al. 2022

Front. Pharmacol.

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Diabetic nephropathy (DN) is the main cause of end-stage renal disease (ESRD), which is characterized by a series of abnormal changes such as glomerulosclerosis, podocyte loss, renal tubular atrophy and excessive deposition of extracellular matrix. Simultaneously, the occurrence of inflammatory reaction can promote the aggravation of DN-induced kidney injury. The most important processes in the canonical inflammasome pathway are inflammasome activation and membrane pore formation mediated by gasdermin family. Converging studies shows that pyroptosis can occur in renal intrinsic cells and participate in the development of DN, and its activation mechanism involves a variety of signaling pathways. Meanwhile, the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome can not only lead to the occurrence of inflammatory response, but also induce pyroptosis. In addition, a number of drugs targeting pyroptosis-associated proteins have been shown to have potential for treating DN. Consequently, the pathogenesis of pyroptosis and several possible activation pathways of NLRP3 inflammasome were reviewed, and the potential drugs used to treat pyroptosis in DN were summarized in this review. Although relevant studies are still not thorough and comprehensive, these findings still have certain reference value for the understanding, treatment and prognosis of DN.

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Gasdermin D Protects Mouse Podocytes Against High-Glucose-Induced Inflammation and Apoptosis via the C-Jun N-Terminal Kinase (JNK) Pathway

Cited by 10 publications

References 13 publications

Cdc42 upregulation under high glucose induces podocyte apoptosis and impairs β-cell insulin secretion

Cdc42 upregulation under high glucose induces podocyte apoptosis and impairs β-cell insulin secretion

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells

NLRP3-mediated pyroptosis in diabetic nephropathy

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