Downregulation of the kidney glucagon receptor, essential for renal function and systemic homeostasis, contributes to chronic kidney disease
Copyright © 2023 Elsevier Inc. All rights reserved..
The glucagon receptor (GCGR) in the kidney is expressed in nephron tubules. In humans and animal models with chronic kidney disease, renal GCGR expression is reduced. However, the role of kidney GCGR in normal renal function and in disease development has not been addressed. Here, we examined its role by analyzing mice with constitutive or conditional kidney-specific loss of the Gcgr. Adult renal Gcgr knockout mice exhibit metabolic dysregulation and a functional impairment of the kidneys. These mice exhibit hyperaminoacidemia associated with reduced kidney glucose output, oxidative stress, enhanced inflammasome activity, and excess lipid accumulation in the kidney. Upon a lipid challenge, they display maladaptive responses with acute hypertriglyceridemia and chronic proinflammatory and profibrotic activation. In aged mice, kidney Gcgr ablation elicits widespread renal deposition of collagen and fibronectin, indicative of fibrosis. Taken together, our findings demonstrate an essential role of the renal GCGR in normal kidney metabolic and homeostatic functions. Importantly, mice deficient for kidney Gcgr recapitulate some of the key pathophysiological features of chronic kidney disease.
| Errataetall: |
CommentIn: Nat Rev Nephrol. 2024 Apr;20(4):203. - PMID 38424242 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:36 |
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| Enthalten in: |
Cell metabolism - 36(2024), 3 vom: 05. März, Seite 575-597.e7 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, May-Yun [VerfasserIn] |
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| Links: |
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| Themen: |
Chronic kidney disease |
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| Anmerkungen: |
Date Completed 08.03.2024 Date Revised 30.03.2024 published: Print-Electronic CommentIn: Nat Rev Nephrol. 2024 Apr;20(4):203. - PMID 38424242 Citation Status MEDLINE |
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| doi: |
10.1016/j.cmet.2023.12.024 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367281015 |
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| 245 | 1 | 0 | |a Downregulation of the kidney glucagon receptor, essential for renal function and systemic homeostasis, contributes to chronic kidney disease |
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| 500 | |a CommentIn: Nat Rev Nephrol. 2024 Apr;20(4):203. - PMID 38424242 | ||
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| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a The glucagon receptor (GCGR) in the kidney is expressed in nephron tubules. In humans and animal models with chronic kidney disease, renal GCGR expression is reduced. However, the role of kidney GCGR in normal renal function and in disease development has not been addressed. Here, we examined its role by analyzing mice with constitutive or conditional kidney-specific loss of the Gcgr. Adult renal Gcgr knockout mice exhibit metabolic dysregulation and a functional impairment of the kidneys. These mice exhibit hyperaminoacidemia associated with reduced kidney glucose output, oxidative stress, enhanced inflammasome activity, and excess lipid accumulation in the kidney. Upon a lipid challenge, they display maladaptive responses with acute hypertriglyceridemia and chronic proinflammatory and profibrotic activation. In aged mice, kidney Gcgr ablation elicits widespread renal deposition of collagen and fibronectin, indicative of fibrosis. Taken together, our findings demonstrate an essential role of the renal GCGR in normal kidney metabolic and homeostatic functions. Importantly, mice deficient for kidney Gcgr recapitulate some of the key pathophysiological features of chronic kidney disease | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a chronic kidney disease | |
| 650 | 4 | |a glucagon receptor | |
| 650 | 4 | |a kidney | |
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| 650 | 7 | |a Lipids |2 NLM | |
| 700 | 1 | |a Zhang, Zhuzhen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Shangang |e verfasserin |4 aut | |
| 700 | 1 | |a Onodera, Toshiharu |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xue-Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Qingzhang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Na |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shiuhwei |e verfasserin |4 aut | |
| 700 | 1 | |a Paredes, Megan |e verfasserin |4 aut | |
| 700 | 1 | |a Gautron, Laurent |e verfasserin |4 aut | |
| 700 | 1 | |a Charron, Maureen J |e verfasserin |4 aut | |
| 700 | 1 | |a Marciano, Denise K |e verfasserin |4 aut | |
| 700 | 1 | |a Gordillo, Ruth |e verfasserin |4 aut | |
| 700 | 1 | |a Drucker, Daniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Scherer, Philipp E |e verfasserin |4 aut | |
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