Endothelial-specific deletion of connexin 43 improves renal function and structure after acute kidney injury

Abstract Background We have previously reported that the gap junction protein connexin 43 (Cx43) was upregulated in chronic renal disease in humans and rodents and plays a crucial role in the progression of experimental nephropathy. In this study, we investigated its role after renal ischemia/reperf...

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Main Authors: Magali Genest, Satoshi Kinugasa, Elena Roger, Louis Boutin, Sandrine Placier, Stefanny Figueroa, Aude Dorison, Safia Hadjadj, Ines Baba, Emmanuel L. Gautier, Panagiotis Kavvadas, Christos Chatziantoniou, Christos E. Chadjichristos
Format: Article
Language:English
Published: BMC 2024-12-01
Series:Molecular Medicine
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Online Access:https://doi.org/10.1186/s10020-024-01011-6
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author Magali Genest
Satoshi Kinugasa
Elena Roger
Louis Boutin
Sandrine Placier
Stefanny Figueroa
Aude Dorison
Safia Hadjadj
Ines Baba
Emmanuel L. Gautier
Panagiotis Kavvadas
Christos Chatziantoniou
Christos E. Chadjichristos
author_facet Magali Genest
Satoshi Kinugasa
Elena Roger
Louis Boutin
Sandrine Placier
Stefanny Figueroa
Aude Dorison
Safia Hadjadj
Ines Baba
Emmanuel L. Gautier
Panagiotis Kavvadas
Christos Chatziantoniou
Christos E. Chadjichristos
author_sort Magali Genest
collection DOAJ
description Abstract Background We have previously reported that the gap junction protein connexin 43 (Cx43) was upregulated in chronic renal disease in humans and rodents and plays a crucial role in the progression of experimental nephropathy. In this study, we investigated its role after renal ischemia/reperfusion (rIR), which is a major mechanism of injury in acute renal injury (AKI) and renal transplant graft dysfunction. Methods Wild-type mice (WT) and mice in which Cx43 expression was genetically reduced by half (Cx43 ±) were unilaterally nephrectomized. The left renal artery was subsequently clamped, with reperfusion of varying duration. Mice with tubular- or endothelial-specific deletion of Cx43 were also used to assess the effect of this connexin in each cell type after rIR. Kidneys were assessed for histological evaluation, immunohistochemistry, and RT-PCR. Results Blood urea nitrogen and creatininemia were progressively elevated in WT mice and picked up 48 h after rIR. At the same time point, severe tubular necrosis and dilation occurred in the cortico-medullary junction of the injured kidneys with accompanying massive neutrophil infiltration. Interestingly, Cx43 expression was progressively increased within the tubulointerstitial compartment during kidney damage progression and was paralleled closely by that of markers of renal dysfunction. Cx43 ± mice showed fewer tubular lesions, less inflammation, and further improved renal function. Similar results were observed in mice where Cx43 was specifically deleted within the vascular endothelium. In contrast, Cx43 deletion in renal tubules did not significantly improve renal structure and function after rIR. Conclusion Our findings suggest that endothelial Cx43 plays a crucial role in AKI.
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spelling doaj-art-83836f98d35c4a929e8c9c96697b0c4c2024-12-22T12:32:15ZengBMCMolecular Medicine1528-36582024-12-0130111410.1186/s10020-024-01011-6Endothelial-specific deletion of connexin 43 improves renal function and structure after acute kidney injuryMagali Genest0Satoshi Kinugasa1Elena Roger2Louis Boutin3Sandrine Placier4Stefanny Figueroa5Aude Dorison6Safia Hadjadj7Ines Baba8Emmanuel L. Gautier9Panagiotis Kavvadas10Christos Chatziantoniou11Christos E. Chadjichristos12Batiment Recherche, INSERM UMR S1155, Tenon HospitalBatiment Recherche, INSERM UMR S1155, Tenon HospitalBatiment Recherche, INSERM UMR S1155, Tenon HospitalBatiment Recherche, INSERM UMR S1155, Tenon HospitalBatiment Recherche, INSERM UMR S1155, Tenon HospitalBatiment Recherche, INSERM UMR S1155, Tenon HospitalBatiment Recherche, INSERM UMR S1155, Tenon HospitalBatiment Recherche, INSERM UMR S1155, Tenon HospitalINSERM, UMR S1166, Sorbonne University, Pitié-Salpétrière HospitalINSERM, UMR S1166, Sorbonne University, Pitié-Salpétrière HospitalBatiment Recherche, INSERM UMR S1155, Tenon HospitalBatiment Recherche, INSERM UMR S1155, Tenon HospitalBatiment Recherche, INSERM UMR S1155, Tenon HospitalAbstract Background We have previously reported that the gap junction protein connexin 43 (Cx43) was upregulated in chronic renal disease in humans and rodents and plays a crucial role in the progression of experimental nephropathy. In this study, we investigated its role after renal ischemia/reperfusion (rIR), which is a major mechanism of injury in acute renal injury (AKI) and renal transplant graft dysfunction. Methods Wild-type mice (WT) and mice in which Cx43 expression was genetically reduced by half (Cx43 ±) were unilaterally nephrectomized. The left renal artery was subsequently clamped, with reperfusion of varying duration. Mice with tubular- or endothelial-specific deletion of Cx43 were also used to assess the effect of this connexin in each cell type after rIR. Kidneys were assessed for histological evaluation, immunohistochemistry, and RT-PCR. Results Blood urea nitrogen and creatininemia were progressively elevated in WT mice and picked up 48 h after rIR. At the same time point, severe tubular necrosis and dilation occurred in the cortico-medullary junction of the injured kidneys with accompanying massive neutrophil infiltration. Interestingly, Cx43 expression was progressively increased within the tubulointerstitial compartment during kidney damage progression and was paralleled closely by that of markers of renal dysfunction. Cx43 ± mice showed fewer tubular lesions, less inflammation, and further improved renal function. Similar results were observed in mice where Cx43 was specifically deleted within the vascular endothelium. In contrast, Cx43 deletion in renal tubules did not significantly improve renal structure and function after rIR. Conclusion Our findings suggest that endothelial Cx43 plays a crucial role in AKI.https://doi.org/10.1186/s10020-024-01011-6Connexin 43InflammationAcute kidney injury
spellingShingle Magali Genest
Satoshi Kinugasa
Elena Roger
Louis Boutin
Sandrine Placier
Stefanny Figueroa
Aude Dorison
Safia Hadjadj
Ines Baba
Emmanuel L. Gautier
Panagiotis Kavvadas
Christos Chatziantoniou
Christos E. Chadjichristos
Endothelial-specific deletion of connexin 43 improves renal function and structure after acute kidney injury
Molecular Medicine
Connexin 43
Inflammation
Acute kidney injury
title Endothelial-specific deletion of connexin 43 improves renal function and structure after acute kidney injury
title_full Endothelial-specific deletion of connexin 43 improves renal function and structure after acute kidney injury
title_fullStr Endothelial-specific deletion of connexin 43 improves renal function and structure after acute kidney injury
title_full_unstemmed Endothelial-specific deletion of connexin 43 improves renal function and structure after acute kidney injury
title_short Endothelial-specific deletion of connexin 43 improves renal function and structure after acute kidney injury
title_sort endothelial specific deletion of connexin 43 improves renal function and structure after acute kidney injury
topic Connexin 43
Inflammation
Acute kidney injury
url https://doi.org/10.1186/s10020-024-01011-6
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