CD248 induces a maladaptive unfolded protein response in diabetic kidney disease
Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved..
Dysfunction of mesangial cells plays a major role in the pathogenesis of diabetic kidney disease (DKD), the leading cause of kidney failure. However, the underlying molecular mechanisms are incompletely understood. By unbiased gene expression analysis of glucose-exposed mesangial cells, we identified the transmembrane receptor CD248 as the most upregulated gene, and the maladaptive unfolded protein response (UPR) as one of the most stimulated pathways. Upregulation of CD248 was further confirmed in glucose-stressed mesangial cells in vitro, in kidney glomeruli isolated from diabetic mice (streptozotocin; STZ and db/db models, representing type 1 and type 2 diabetes mellitus, respectively) in vivo, and in glomerular kidney sections from patients with DKD. Time course analysis revealed that glomerular CD248 induction precedes the onset of albuminuria, mesangial matrix expansion and maladaptive UPR activation (hallmarked by transcription factor C/EBP homologous protein (CHOP) induction) but is paralleled by loss of the adaptive UPR regulator spliced X box binding protein (XBP1). Mechanistically, CD248 promoted maladaptive UPR signaling via inhibition of the inositol requiring enzyme 1α (IRE1α)-mediated transcription factor XBP1 splicing in vivo and in vitro. CD248 induced a multiprotein complex comprising heat shock protein 90, BH3 interacting domain death agonist (BID) and IRE1α, in which BID impedes IRE1α-mediated XBP1 splicing and induced CHOP mediated maladaptive UPR signaling. While CD248 knockout ameliorated DKD-associated glomerular dysfunction and reverses maladaptive unfolded protein response signaling, concomitant XBP1 deficiency abolished the protective effect in diabetic CD248 knockout mice, supporting a functional interaction of CD248 and XBP1 in vivo. Hence, CD248 is a novel mesangial cell receptor inducing maladaptive UPR signaling in DKD.
| Errataetall: |
CommentIn: Kidney Int. 2023 Feb;103(2):254-256. - PMID 36681453 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:103 |
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| Enthalten in: |
Kidney international - 103(2023), 2 vom: 27. Feb., Seite 304-319 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Krishnan, Shruthi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.01.2023 Date Revised 22.11.2023 published: Print-Electronic CommentIn: Kidney Int. 2023 Feb;103(2):254-256. - PMID 36681453 Citation Status MEDLINE |
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| doi: |
10.1016/j.kint.2022.09.024 |
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| 500 | |a CommentIn: Kidney Int. 2023 Feb;103(2):254-256. - PMID 36681453 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Dysfunction of mesangial cells plays a major role in the pathogenesis of diabetic kidney disease (DKD), the leading cause of kidney failure. However, the underlying molecular mechanisms are incompletely understood. By unbiased gene expression analysis of glucose-exposed mesangial cells, we identified the transmembrane receptor CD248 as the most upregulated gene, and the maladaptive unfolded protein response (UPR) as one of the most stimulated pathways. Upregulation of CD248 was further confirmed in glucose-stressed mesangial cells in vitro, in kidney glomeruli isolated from diabetic mice (streptozotocin; STZ and db/db models, representing type 1 and type 2 diabetes mellitus, respectively) in vivo, and in glomerular kidney sections from patients with DKD. Time course analysis revealed that glomerular CD248 induction precedes the onset of albuminuria, mesangial matrix expansion and maladaptive UPR activation (hallmarked by transcription factor C/EBP homologous protein (CHOP) induction) but is paralleled by loss of the adaptive UPR regulator spliced X box binding protein (XBP1). Mechanistically, CD248 promoted maladaptive UPR signaling via inhibition of the inositol requiring enzyme 1α (IRE1α)-mediated transcription factor XBP1 splicing in vivo and in vitro. CD248 induced a multiprotein complex comprising heat shock protein 90, BH3 interacting domain death agonist (BID) and IRE1α, in which BID impedes IRE1α-mediated XBP1 splicing and induced CHOP mediated maladaptive UPR signaling. While CD248 knockout ameliorated DKD-associated glomerular dysfunction and reverses maladaptive unfolded protein response signaling, concomitant XBP1 deficiency abolished the protective effect in diabetic CD248 knockout mice, supporting a functional interaction of CD248 and XBP1 in vivo. Hence, CD248 is a novel mesangial cell receptor inducing maladaptive UPR signaling in DKD | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CD248 | |
| 650 | 4 | |a CHOP | |
| 650 | 4 | |a diabetic kidney disease | |
| 650 | 4 | |a glomerular damage | |
| 650 | 4 | |a mesangial cells | |
| 650 | 4 | |a sXBP1 | |
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| 650 | 7 | |a Antigens, Neoplasm |2 NLM | |
| 650 | 7 | |a CD248 protein, mouse |2 NLM | |
| 650 | 7 | |a Endoribonucleases |2 NLM | |
| 650 | 7 | |a EC 3.1.- |2 NLM | |
| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 700 | 1 | |a Manoharan, Jayakumar |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hongjie |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Dheerendra |e verfasserin |4 aut | |
| 700 | 1 | |a Fatima, Sameen |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Yanfei |e verfasserin |4 aut | |
| 700 | 1 | |a Mathew, Akash |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Kohli, Shrey |e verfasserin |4 aut | |
| 700 | 1 | |a Schwab, Constantin |e verfasserin |4 aut | |
| 700 | 1 | |a Körner, Antje |e verfasserin |4 aut | |
| 700 | 1 | |a Mertens, Peter R |e verfasserin |4 aut | |
| 700 | 1 | |a Nawroth, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Shahzad, Khurrum |e verfasserin |4 aut | |
| 700 | 1 | |a Naumann, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Isermann, Berend |e verfasserin |4 aut | |
| 700 | 1 | |a Biemann, Ronald |e verfasserin |4 aut | |
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