HNF-1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasis
Objective The current study aims to elucidate the critical function of hepatocyte nuclear factor 1-beta (HNF1-β) in lupus nephritis (LN) by investigating its modulation of the Derlin-1/valosin-containing protein (VCP)/VCP-interacting membrane selenoprotein (VIMP) complex, endoplasmic reticulum (ER)...
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BMJ Publishing Group
2024-12-01
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| Series: | Lupus Science and Medicine |
| Online Access: | https://lupus.bmj.com/content/11/2/e001349.full |
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| author | Jie Yu Bing Guo Fan Zhang Miao Liu Ying Xie Hui-mei Zou Yuan-yuan Ruan Xiao-min An Pei-lei Chen Ying-qin Luo Ming-jun Shi Li-fen Xu |
| author_facet | Jie Yu Bing Guo Fan Zhang Miao Liu Ying Xie Hui-mei Zou Yuan-yuan Ruan Xiao-min An Pei-lei Chen Ying-qin Luo Ming-jun Shi Li-fen Xu |
| author_sort | Jie Yu |
| collection | DOAJ |
| description | Objective The current study aims to elucidate the critical function of hepatocyte nuclear factor 1-beta (HNF1-β) in lupus nephritis (LN) by investigating its modulation of the Derlin-1/valosin-containing protein (VCP)/VCP-interacting membrane selenoprotein (VIMP) complex, endoplasmic reticulum (ER) stress and podocyte apoptosis.Methods In vitro and in vivo models of LN were established using glomerular podocytes treated with LN serum and MRL/lpr mice, respectively. The expression levels of HNF1-β were analysed in kidney tissues from patients with LN and MRL/lpr mice. To assess the effects of HNF1-β inhibition, an adeno-associated virus vector carrying HNF1-β short hairpin was administered to MRL/lpr mice. In vitro, glomerular podocytes were transfected with HNF1-β small interfering RNA (siRNA) or HNF1-β overexpression plasmids to explore their regulatory effects on the Derlin-1/VCP/VIMP complex and podocyte apoptosis. Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were performed to investigate the transcriptional activation of Derlin-1 and VCP promoters by HNF1-β.Results A significant decrease in HNF1-β levels was observed in kidney tissues from patients with LN while MRL/lpr mice exhibited an initial compensatory increase followed by a subsequent decrease in renal HNF1-β expression. Overexpression of HNF1-β transcriptionally upregulated Derlin-1 and VCP mitigating LN serum-induced ER stress and podocyte apoptosis. In contrast, HNF1-β inhibition exacerbated renal dysfunction and structural damage in MRL/lpr mice. Interestingly, HNF1-β inhibition transcriptionally repressed ERP44, leading to calcium ions (Ca²+) release-mediated disruption and inactivation of the Derlin-1/VCP/VIMP complex. This finding suggests that HNF1-β not only regulates the expression of key proteins in the Derlin-1/VCP/VIMP complex but also influences their assembly through Ca²+ release regulation.Conclusion This study provides novel insights into the regulatory mechanisms of HNF1-β in LN emphasising its impact on the Derlin-1/VCP/VIMP complex, ER stress and podocyte apoptosis. These findings have the potential to inform the development of new diagnostic tools and therapeutic strategies for LN. |
| format | Article |
| id | doaj-art-8f22fbc92f04417db9a4180832effdfe |
| institution | OA Journals |
| issn | 2053-8790 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Lupus Science and Medicine |
| spelling | doaj-art-8f22fbc92f04417db9a4180832effdfe2025-08-20T01:55:32ZengBMJ Publishing GroupLupus Science and Medicine2053-87902024-12-0111210.1136/lupus-2024-001349HNF-1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasisJie Yu0Bing Guo1Fan Zhang2Miao Liu3Ying Xie4Hui-mei Zou5Yuan-yuan Ruan6Xiao-min An7Pei-lei Chen8Ying-qin Luo9Ming-jun Shi10Li-fen Xu11Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, ChinaDepartment of Pathophysiology, Guizhou Medical University, Guiyang, ChinaDepartment of Pathophysiology, Guizhou Medical University, Guiyang, ChinaDepartment of Urinary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, ChinaDepartment of Pathophysiology, Guizhou Medical University, Guiyang, ChinaDepartment of Pathophysiology, Guizhou Medical University, Guiyang, ChinaDepartment of Pathophysiology, Guizhou Medical University, Guiyang, ChinaDepartment of Pathophysiology, Guizhou Medical University, Guiyang, ChinaDepartment of Pathophysiology, Guizhou Medical University, Guiyang, ChinaDepartment of Pathophysiology, Guizhou Medical University, Guiyang, ChinaDepartment of Pathophysiology, Guizhou Medical University, Guiyang, ChinaDepartment of Pathology, The Affiliated Hospital of Guizhou Medical University, Guiyang, ChinaObjective The current study aims to elucidate the critical function of hepatocyte nuclear factor 1-beta (HNF1-β) in lupus nephritis (LN) by investigating its modulation of the Derlin-1/valosin-containing protein (VCP)/VCP-interacting membrane selenoprotein (VIMP) complex, endoplasmic reticulum (ER) stress and podocyte apoptosis.Methods In vitro and in vivo models of LN were established using glomerular podocytes treated with LN serum and MRL/lpr mice, respectively. The expression levels of HNF1-β were analysed in kidney tissues from patients with LN and MRL/lpr mice. To assess the effects of HNF1-β inhibition, an adeno-associated virus vector carrying HNF1-β short hairpin was administered to MRL/lpr mice. In vitro, glomerular podocytes were transfected with HNF1-β small interfering RNA (siRNA) or HNF1-β overexpression plasmids to explore their regulatory effects on the Derlin-1/VCP/VIMP complex and podocyte apoptosis. Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were performed to investigate the transcriptional activation of Derlin-1 and VCP promoters by HNF1-β.Results A significant decrease in HNF1-β levels was observed in kidney tissues from patients with LN while MRL/lpr mice exhibited an initial compensatory increase followed by a subsequent decrease in renal HNF1-β expression. Overexpression of HNF1-β transcriptionally upregulated Derlin-1 and VCP mitigating LN serum-induced ER stress and podocyte apoptosis. In contrast, HNF1-β inhibition exacerbated renal dysfunction and structural damage in MRL/lpr mice. Interestingly, HNF1-β inhibition transcriptionally repressed ERP44, leading to calcium ions (Ca²+) release-mediated disruption and inactivation of the Derlin-1/VCP/VIMP complex. This finding suggests that HNF1-β not only regulates the expression of key proteins in the Derlin-1/VCP/VIMP complex but also influences their assembly through Ca²+ release regulation.Conclusion This study provides novel insights into the regulatory mechanisms of HNF1-β in LN emphasising its impact on the Derlin-1/VCP/VIMP complex, ER stress and podocyte apoptosis. These findings have the potential to inform the development of new diagnostic tools and therapeutic strategies for LN.https://lupus.bmj.com/content/11/2/e001349.full |
| spellingShingle | Jie Yu Bing Guo Fan Zhang Miao Liu Ying Xie Hui-mei Zou Yuan-yuan Ruan Xiao-min An Pei-lei Chen Ying-qin Luo Ming-jun Shi Li-fen Xu HNF-1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasis Lupus Science and Medicine |
| title | HNF-1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasis |
| title_full | HNF-1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasis |
| title_fullStr | HNF-1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasis |
| title_full_unstemmed | HNF-1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasis |
| title_short | HNF-1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasis |
| title_sort | hnf 1β alleviates podocyte injury in lupus nephritis by maintaining endoplasmic reticulum homeostasis |
| url | https://lupus.bmj.com/content/11/2/e001349.full |
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