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Neutrophil extracellular traps induce glomerular endothelial cell dysfunction and pyroptosis in diabetic kidney disease

ABSTRACT: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Neutrophil extracellular traps (NETs) are a network structure composed of loose chromatin and embedded with multiple proteins. Here, we observed increased NETs deposition in the glomeruli of DKD patients and diabetic mice (streptozotocin-induced or db/db mice). After degrading NETs with DNase I, diabetic mice exhibited attenuated glomerulopathy and glomerular endothelial cell (GEC) injury. We also observed alleviated glomerulopathy and GEC injury in peptidylarginine deiminase 4 (PAD4)-knockout mice with streptozotocin-induced diabetes. In vitro, NET-induced GEC pyroptosis was characterized by pore formation in the cell membrane, dysregulation of multiple genes involved in cell membrane function, and high expression of pyroptosis-related proteins. Strengthening the GEC surface charge by oleylamine significantly inhibited NET-induced GEC pyroptosis. These results indicate that NET-induced alterations in GEC charge are associated with GEC pyroptosis in the pathogenesis of DKD and suggest that NETs are a potential therapeutic target for DKD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189875 | GEO | 2022/09/01

REPOSITORIES: GEO

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Project description:Dyslipidemia is a significant risk factor for progression of diabetic kidney disease (DKD). To identify individual lipids and lipid networks that may be involved in DKD progression, we performed untargeted lipidomic analysis of kidney cortex tissue from diabetic db/db and db/db eNOS-/- mice along with nondiabetic littermate controls. A subset of mice were treated with the renin-angiotensin system (RAS) inhibitors, lisinopril and losartan, which improves the DKD phenotype in the db/db eNOS-/- mouse model. Of the three independent variables in this study, diabetes had the largest impact on overall lipid levels in the kidney cortex, while eNOS expression and RAS inhibition had smaller impacts on kidney lipid levels. Kidney lipid network architecture, particularly of networks involving glycerolipids such as triacylglycerols, was substantially disrupted by worsening kidney disease in the db/db eNOS-/- mice compared to the db/db mice, a feature that was reversed with RAS inhibition. This was associated with decreased expression of the stearoyl-CoA desaturases, Scd1 and Scd2, with RAS inhibition. In addition to the known salutary effect of RAS inhibition on DKD progression, our results suggest a previously unrecognized role for RAS inhibition on the kidney triacylglycerol lipid metabolic network. Keywords: Dyslipidemia is a significant risk factor for progression of diabetic kidney disease (DKD). To identify individual lipids and lipid networks that may be involved in DKD progression, we performed untargeted lipidomic analysis of kidney cortex tissue from diabetic db/db and db/db eNOS-/- mice along with non-diabetic littermate controls. A subset of mice were treated with the renin-angiotensin system (RAS) inhibitors, lisinopril and losartan, which improves the DKD phenotype in the db/db eNOS-/- mouse model. Of the three independent variables in this study, diabetes had the largest impact on overall lipid levels in the kidney cortex, while eNOS expression and RAS inhibition had smaller impacts on kidney lipid levels. Kidney lipid network architecture, particularly of networks involving glycerolipids such as triacylglycerols, was substantially disrupted by worsening kidney disease in the db/db eNOS-/- mice compared to the db/db mice, a feature that was reversed with RAS inhibition. This was associated with decreased expression of the stearoyl-CoA desaturases, Scd1 and Scd2, with RAS inhibition. In addition to the known salutary effect of RAS inhibition on DKD progression, our results suggest a previously unrecognized role for RAS inhibition on the kidney triacylglycerol lipid metabolic network.

Project description:Purpose: Our study clarifies the mechanism of Huangqi decoction (HQD) against DKD in diabetic db/db mice. Methods: Eight-week-old male diabetic db/db mice were randomly divided into four groups: Model (1% CMC), HQD-L (0.12 g/kg), HQD-M (0.36 g/kg), and HQD-H (1.08 g/kg) groups. Non-diabetic db/m mice were used as a control group. These mice received HQD treatment for 8 weeks continuously. After 8 weeks of feeding, kidneys were harvested to observe the kidney function, pathological changes, micro-assay study, and the protein expression levels. Results: HQD treatment improved the albumin/creatine ratio (ACR) and 24 h urinary albumin, prevented the pathological phenotypes of increased glomerular volume, widened mesangial areas, the proliferation of mesangial matrix, the disappearance of foot processes, the decreased expression of nephrin and the number of podocytes. The expression profile chips were assessed to reveal the global transcriptional response and predict related functions, diseases and pathways. To verify this, we found that HQD treatment activated the protein expressions of BMP1, BMP7, BMPR2, and active-Rap1 and inhibited Smad1 and phospho-ERK. In addition, HQD could improve lipid deposition in the kidneys of db/db mice. Conclusion: HQD prevents the progression of DKD in db/db mice by regulating the transcription of BMPs and their downstream target genes, inhibiting the phosphorylation of ERK and Smad1 by promoting the binding of Rap1 to GTP and regulating the lipid metabolism dysfunction. These provide a new idea for the treatment of DKD. Overall, HQD had a significant protective effect against DKD. This may be related to the fact that HQD promotes the transcription of BMPs and their downstream target genes by upregulating BMPR-II and regulates the phosphorylation of ERK and Smad by promoting the binding of Rap1 to GTP. In addition, HQD also has a noticeable role in regulating lipid metabolism dysfunction in DKD, which provides a new idea for future research on HQD.

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Neutrophil extracellular traps induce glomerular endothelial cell dysfunction and pyroptosis in diabetic kidney disease

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