Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease
Abstract 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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-03-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-024-01565-2 |
| _version_ | 1797233465172688896 |
|---|---|
| author | Siyuan Cui Xin Chen Jiayu Li Wei Wang Deqi Meng Shenglong Zhu Shiwei Shen |
| author_facet | Siyuan Cui Xin Chen Jiayu Li Wei Wang Deqi Meng Shenglong Zhu Shiwei Shen |
| author_sort | Siyuan Cui |
| collection | DOAJ |
| description | Abstract 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-Cxcr2 eCKO 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 Cxcr2 L/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. |
| first_indexed | 2024-04-24T16:16:36Z |
| format | Article |
| id | doaj.art-78177dfc17304ff2bdc760c6c236afe4 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-04-24T16:16:36Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-78177dfc17304ff2bdc760c6c236afe42024-03-31T11:26:56ZengBMCCell Communication and Signaling1478-811X2024-03-0122111910.1186/s12964-024-01565-2Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney diseaseSiyuan Cui0Xin Chen1Jiayu Li2Wei Wang3Deqi Meng4Shenglong Zhu5Shiwei Shen6Department of Endocrinology, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical UniversityDepartment of Endocrinology, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical UniversityWuxi School of Medicine, Jiangnan UniversityWuxi School of Medicine, Jiangnan UniversityDepartment of Endocrinology, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical UniversityWuxi School of Medicine, Jiangnan UniversityDepartment of Endocrinology, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical UniversityAbstract 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-Cxcr2 eCKO 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 Cxcr2 L/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.https://doi.org/10.1186/s12964-024-01565-2CXCR2Diabetic kidney diseaseInflammationGlycocalyx sheddingNF-κB signaling |
| spellingShingle | Siyuan Cui Xin Chen Jiayu Li Wei Wang Deqi Meng Shenglong Zhu Shiwei Shen Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease Cell Communication and Signaling CXCR2 Diabetic kidney disease Inflammation Glycocalyx shedding NF-κB signaling |
| title | Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease |
| title_full | Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease |
| title_fullStr | Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease |
| title_full_unstemmed | Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease |
| title_short | Endothelial CXCR2 deficiency attenuates renal inflammation and glycocalyx shedding through NF-κB signaling in diabetic kidney disease |
| title_sort | endothelial cxcr2 deficiency attenuates renal inflammation and glycocalyx shedding through nf κb signaling in diabetic kidney disease |
| topic | CXCR2 Diabetic kidney disease Inflammation Glycocalyx shedding NF-κB signaling |
| url | https://doi.org/10.1186/s12964-024-01565-2 |
| work_keys_str_mv | AT siyuancui endothelialcxcr2deficiencyattenuatesrenalinflammationandglycocalyxsheddingthroughnfkbsignalingindiabetickidneydisease AT xinchen endothelialcxcr2deficiencyattenuatesrenalinflammationandglycocalyxsheddingthroughnfkbsignalingindiabetickidneydisease AT jiayuli endothelialcxcr2deficiencyattenuatesrenalinflammationandglycocalyxsheddingthroughnfkbsignalingindiabetickidneydisease AT weiwang endothelialcxcr2deficiencyattenuatesrenalinflammationandglycocalyxsheddingthroughnfkbsignalingindiabetickidneydisease AT deqimeng endothelialcxcr2deficiencyattenuatesrenalinflammationandglycocalyxsheddingthroughnfkbsignalingindiabetickidneydisease AT shenglongzhu endothelialcxcr2deficiencyattenuatesrenalinflammationandglycocalyxsheddingthroughnfkbsignalingindiabetickidneydisease AT shiweishen endothelialcxcr2deficiencyattenuatesrenalinflammationandglycocalyxsheddingthroughnfkbsignalingindiabetickidneydisease |