Sepsis induces heterogeneous transcription of coagulation- and inflammation-associated genes in renal microvasculature
Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved..
BACKGROUND: Acute kidney injury (AKI) in sepsis patients increases patient mortality. Endothelial cells are important players in the pathophysiology of sepsis-associated AKI (SA-AKI), yet knowledge regarding their spatiotemporal involvement in coagulation disbalance and leukocyte recruitment is lacking. This study investigated the identity and kinetics of responses of different microvascular compartments in kidney cortex in response to SA-AKI.
METHODS: Laser microdissected arterioles, glomeruli, peritubular capillaries, and postcapillary venules from kidneys of mice subjected to cecal ligation and puncture (CLP) were analyzed using RNA sequencing. Differential expression and pathway enrichment analyses identified genes involved in coagulation and inflammation. A selection of these genes was evaluated by RT-qPCR in microvascular compartments of renal biopsies from patients with SA-AKI. The role of two identified genes in lipopolysaccharide-induced endothelial coagulation and inflammatory activation were determined in vitro in HUVEC using siRNA-based gene silencing.
RESULTS: CLP-sepsis in mice induced altered expression of approximately 400 genes in the renal microvasculature, with microvascular compartments exhibiting unique spatiotemporal responses. In mice, changes in gene expression related to coagulation and inflammation were most extensive in glomeruli at early and intermediate time points, with high induction of Plat, Serpine1, Thbd, Icam1, Stat3, and Ifitm3. In human SA-AKI, PROCR and STAT3 were induced in postcapillary venules, while SERPINE1 expression was diminished. IFITM3 was increased in arterioles and glomeruli. In vitro studies revealed that STAT3 and IFITM3 partly control endothelial coagulation and inflammatory activation.
CONCLUSION: Renal microvascular compartments in mice and humans exhibited heterogeneous changes in coagulation- and inflammation-related gene expression in response to SA-AKI. Additional research should aim at understanding the functional consequences of the here described heterogeneous microvascular responses to establish the usefulness of identified genes as therapeutic targets in SA-AKI.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:237 |
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| Enthalten in: |
Thrombosis research - 237(2024) vom: 15. Apr., Seite 112-128 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Luxen, Matthijs [VerfasserIn] |
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| Links: |
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| Themen: |
Coagulation |
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| Anmerkungen: |
Date Completed 27.04.2024 Date Revised 27.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.thromres.2024.03.014 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370689240 |
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| 100 | 1 | |a Luxen, Matthijs |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Sepsis induces heterogeneous transcription of coagulation- and inflammation-associated genes in renal microvasculature |
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| 500 | |a published: Print-Electronic | ||
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| 520 | |a Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a BACKGROUND: Acute kidney injury (AKI) in sepsis patients increases patient mortality. Endothelial cells are important players in the pathophysiology of sepsis-associated AKI (SA-AKI), yet knowledge regarding their spatiotemporal involvement in coagulation disbalance and leukocyte recruitment is lacking. This study investigated the identity and kinetics of responses of different microvascular compartments in kidney cortex in response to SA-AKI | ||
| 520 | |a METHODS: Laser microdissected arterioles, glomeruli, peritubular capillaries, and postcapillary venules from kidneys of mice subjected to cecal ligation and puncture (CLP) were analyzed using RNA sequencing. Differential expression and pathway enrichment analyses identified genes involved in coagulation and inflammation. A selection of these genes was evaluated by RT-qPCR in microvascular compartments of renal biopsies from patients with SA-AKI. The role of two identified genes in lipopolysaccharide-induced endothelial coagulation and inflammatory activation were determined in vitro in HUVEC using siRNA-based gene silencing | ||
| 520 | |a RESULTS: CLP-sepsis in mice induced altered expression of approximately 400 genes in the renal microvasculature, with microvascular compartments exhibiting unique spatiotemporal responses. In mice, changes in gene expression related to coagulation and inflammation were most extensive in glomeruli at early and intermediate time points, with high induction of Plat, Serpine1, Thbd, Icam1, Stat3, and Ifitm3. In human SA-AKI, PROCR and STAT3 were induced in postcapillary venules, while SERPINE1 expression was diminished. IFITM3 was increased in arterioles and glomeruli. In vitro studies revealed that STAT3 and IFITM3 partly control endothelial coagulation and inflammatory activation | ||
| 520 | |a CONCLUSION: Renal microvascular compartments in mice and humans exhibited heterogeneous changes in coagulation- and inflammation-related gene expression in response to SA-AKI. Additional research should aim at understanding the functional consequences of the here described heterogeneous microvascular responses to establish the usefulness of identified genes as therapeutic targets in SA-AKI | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Coagulation | |
| 650 | 4 | |a Endothelial heterogeneity | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Renal microvascular compartments | |
| 650 | 4 | |a Sepsis-associated acute kidney injury | |
| 650 | 4 | |a Transcriptome | |
| 700 | 1 | |a Zwiers, Peter J |e verfasserin |4 aut | |
| 700 | 1 | |a Jongman, Rianne M |e verfasserin |4 aut | |
| 700 | 1 | |a Moser, Jill |e verfasserin |4 aut | |
| 700 | 1 | |a Pultar, Marianne |e verfasserin |4 aut | |
| 700 | 1 | |a Skalicky, Susanna |e verfasserin |4 aut | |
| 700 | 1 | |a Diendorfer, Andreas B |e verfasserin |4 aut | |
| 700 | 1 | |a Hackl, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a van Meurs, Matijs |e verfasserin |4 aut | |
| 700 | 1 | |a Molema, Grietje |e verfasserin |4 aut | |
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