PLVAP as an Early Marker of Glomerular Endothelial Damage in Mice with Diabetic Kidney Disease

Wolf, Elena E.; Steglich, Anne; Kessel, Friederike; Kröger, Hannah; Sradnick, Jan; Reichelt-Wurm, Simone; Eidenschink, Kathrin; Banas, Miriam C.; Wolf, Eckhard; Wanke, Rüdiger; Gembardt, Florian; Todorov, Vladimir

doi:10.3390/ijms24021094

Cited by 2 publications

(2 citation statements)

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“…In the context of DKD, both endothelial dysfunction and inflammation are recognized as contributors to disease progression [ 55 – 58 ]. However, the specific relationship between endothelial inflammation and glycocalyx shedding in DKD remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease

Cui,

Chen,

et al. 2024

Cell Commun Signal

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Background The incidence of diabetic kidney disease (DKD) continues to rapidly increase, with limited available treatment options. One of the hallmarks of DKD is persistent inflammation, but the underlying molecular mechanisms of early diabetic kidney injury remain poorly understood. C-X-C chemokine receptor 2 (CXCR2), plays an important role in the progression of inflammation-related vascular diseases and may bridge between glomerular endothelium and persistent inflammation in DKD. Methods Multiple methods were employed to assess the expression levels of CXCR2 and its ligands, as well as renal inflammatory response and endothelial glycocalyx shedding in patients with DKD. The effects of CXCR2 on glycocalyx shedding, and persistent renal inflammation was examined in a type 2 diabetic mouse model with Cxcr2 knockout specifically in endothelial cells (DKD-Cxcr2eCKO mice), as well as in glomerular endothelial cells (GECs), cultured in high glucose conditions. Results CXCR2 was associated with early renal decline in DKD patients, and endothelial-specific knockout of CXCR2 significantly improved renal function in DKD mice, reduced inflammatory cell infiltration, and simultaneously decreased the expression of proinflammatory factors and chemokines in renal tissue. In DKD conditions, glycocalyx shedding was suppressed in endothelial Cxcr2 knockout mice compared to Cxcr2L/L mice. Modulating CXCR2 expression also affected high glucose-induced inflammation and glycocalyx shedding in GECs. Mechanistically, CXCR2 deficiency inhibited the activation of NF-κB signaling, thereby regulating inflammation, restoring the endothelial glycocalyx, and alleviating DKD. Conclusions Taken together, under DKD conditions, activation of CXCR2 exacerbates inflammation through regulation of the NF-κB pathway, leading to endothelial glycocalyx shedding and deteriorating renal function. Endothelial CXCR2 deficiency has a protective role in inflammation and glycocalyx dysfunction, suggesting its potential as a promising therapeutic target for DKD treatment.

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Section: Discussionmentioning

confidence: 99%

Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease

Cui,

Chen,

et al. 2024

Cell Commun Signal

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“…The PLVAP protein is the main component of endothelial diaphragms in fenestrae, caveolae, and transendothelial channels, shown in previous studies to be associated with DKD and HCC. On the one hand, PLVAP can be used as an early marker of glomerular endothelial injury with DKD in mice ( 44 ), and do increase in glomeruli of human diabetic patients ( 45 ). On the other hand, PLVAP was identified as a gene expressed explicitly in HCC vascular endothelial cells ( 46 ), and has been investigated as a therapeutic target in HCC ( 46 ), perhaps based on its ability to alter the immunosuppressive microenvironment ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Screening immune-related blood biomarkers for DKD-related HCC using machine learning

Chen,

Xie,

et al. 2024

Front. Immunol.

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BackgroundDiabetes mellitus is a significant health problem worldwide, often leading to diabetic kidney disease (DKD), which may also influence the occurrence of hepatocellular carcinoma (HCC). However, the relationship and diagnostic biomarkers between DKD and HCC are unclear.MethodsUsing public database data, we screened DKD secretory RNAs and HCC essential genes by limma and WGCNA. Potential mechanisms, drugs, and biomarkers for DKD-associated HCC were identified using PPI, functional enrichment, cMAP, and machine learning algorithms, and a diagnostic nomogram was constructed. Then, ROC, calibration, and decision curves were used to evaluate the diagnostic performance of the nomograms. In addition, immune cell infiltration in HCC was explored using CIBERSORT. Finally, the detectability of critical genes in blood was verified by qPCR.Results104 DEGs associated with HCC using WGCNA were identified. 101 DEGs from DKD were predicated on secreting into the bloodstream with Exorbase datasets. PPI analysis identified three critical modules considered causative genes for DKD-associated HCC, primarily involved in inflammation and immune regulation. Using lasso and RM, four hub genes associated with DKD-associated HCC were identified, and a diagnostic nomogram confirmed by DCA curves was established. The results of immune cell infiltration showed immune dysregulation in HCC, which was associated with the expression of four essential genes. PLVAP was validated by qPCR as a possible blood-based diagnostic marker for DKD-related HCC.ConclusionWe revealed the inflammatory immune pathways of DKD-related HCC and developed a diagnostic nomogram for HCC based on PLVAP, C7, COL15A1, and MS4A6A. We confirmed with qPCR that PLVAP can be used as a blood marker to assess the risk of HCC in DKD patients.

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PLVAP as an Early Marker of Glomerular Endothelial Damage in Mice with Diabetic Kidney Disease

Cited by 2 publications

References 47 publications

Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease

Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease

Screening immune-related blood biomarkers for DKD-related HCC using machine learning

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