RAS protein activator-like 2 (RASAL2) initiates peritubular capillary rarefaction in hypoxic renal interstitial fibrosis
Copyright © 2024. Published by Elsevier Inc..
The progression of chronic kidney disease (CKD) often involves renal interstitial fibrosis (RIF) and subsequent loss of peritubular capillaries (PTCs), which enhances disease severity. Despite advancements in our understanding of fibrosis, effective interventions for reversing capillary loss remain elusive. Notably, RIF exhibits reduced capillary density, whereas renal cell carcinoma (RCC) shows robust angiogenesis under hypoxic conditions. Using RNA sequencing and bioinformatics, we identified differentially expressed genes (DEGs) in hypoxic human renal tubular epithelial cells (HK-2) and renal cancer cells (786-0). Analysis of altered Ras and PI3K/Akt pathways coupled with hub gene investigation revealed RAS protein activator-like 2 (RASAL2) as a key candidate. Subsequent in vitro and in vivo studies confirmed RASAL2's early-stage response in RIF, which reduced with fibrosis progression. RASAL2 suppression in HK-2 cells enhanced angiogenesis, as evidenced by increased proliferation, migration, and branching of human umbilical vein endothelial cells (HUVECs) co-cultured with HK-2 cells. In mice, RASAL2 knockdown improved Vascular endothelial growth factor A (VEGFA) and Proliferating cell nuclear antigen (PCNA) levels in unilateral ureteral occlusion (UUO)-induced fibrosis (compared to wild type). Hypoxia-inducible factor 1 alpha (HIF-1α) emerged as a pivotal mediator, substantiated by chromatin immunoprecipitation (ChIP) sequencing, with its induction linked to activation. Hypoxia increased the production of RASAL2-enriched extracellular vesicles (EVs) derived from tubular cells, which were internalized by endothelial cells, contributing to the exacerbation of PTC loss. These findings underscore RASAL2's role in mediating reduced angiogenesis in RIF and reveal a novel EV-mediated communication between hypoxic tubular- and endothelial cells, demonstrating a complex interplay between angiogenesis and fibrosis in CKD pathogenesis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:269 |
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| Enthalten in: |
Translational research : the journal of laboratory and clinical medicine - 269(2024) vom: 05. März, Seite 14-30 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Yu [VerfasserIn] |
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| Links: |
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| Themen: |
Angiogenesis |
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| Anmerkungen: |
Date Revised 28.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1016/j.trsl.2024.03.003 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369428013 |
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| 520 | |a Copyright © 2024. Published by Elsevier Inc. | ||
| 520 | |a The progression of chronic kidney disease (CKD) often involves renal interstitial fibrosis (RIF) and subsequent loss of peritubular capillaries (PTCs), which enhances disease severity. Despite advancements in our understanding of fibrosis, effective interventions for reversing capillary loss remain elusive. Notably, RIF exhibits reduced capillary density, whereas renal cell carcinoma (RCC) shows robust angiogenesis under hypoxic conditions. Using RNA sequencing and bioinformatics, we identified differentially expressed genes (DEGs) in hypoxic human renal tubular epithelial cells (HK-2) and renal cancer cells (786-0). Analysis of altered Ras and PI3K/Akt pathways coupled with hub gene investigation revealed RAS protein activator-like 2 (RASAL2) as a key candidate. Subsequent in vitro and in vivo studies confirmed RASAL2's early-stage response in RIF, which reduced with fibrosis progression. RASAL2 suppression in HK-2 cells enhanced angiogenesis, as evidenced by increased proliferation, migration, and branching of human umbilical vein endothelial cells (HUVECs) co-cultured with HK-2 cells. In mice, RASAL2 knockdown improved Vascular endothelial growth factor A (VEGFA) and Proliferating cell nuclear antigen (PCNA) levels in unilateral ureteral occlusion (UUO)-induced fibrosis (compared to wild type). Hypoxia-inducible factor 1 alpha (HIF-1α) emerged as a pivotal mediator, substantiated by chromatin immunoprecipitation (ChIP) sequencing, with its induction linked to activation. Hypoxia increased the production of RASAL2-enriched extracellular vesicles (EVs) derived from tubular cells, which were internalized by endothelial cells, contributing to the exacerbation of PTC loss. These findings underscore RASAL2's role in mediating reduced angiogenesis in RIF and reveal a novel EV-mediated communication between hypoxic tubular- and endothelial cells, demonstrating a complex interplay between angiogenesis and fibrosis in CKD pathogenesis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Angiogenesis | |
| 650 | 4 | |a Chronic kidney disease (CKD) | |
| 650 | 4 | |a Extracellular vesicles (EVs) | |
| 650 | 4 | |a RASAL2 | |
| 650 | 4 | |a Renal interstitial fibrosis (RIF) | |
| 700 | 1 | |a Yang, Yiqiong |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Xiuxiu |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Bizhen |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Chuanbing |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Pingsheng |e verfasserin |4 aut | |
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