Targeting connexin 43 protects against the progression of experimental chronic kidney disease in mice.
Excessive recruitment of monocytes and progression of fibrosis are hallmarks of chronic kidney disease (CKD). Recently we reported that the expression of connexin 43 (Cx43) was upregulated in the kidney during experimental nephropathy. To investigate the role of Cx43 in the progression of CKD, we interbred RenTg mice, a genetic model of hypertension-induced CKD, with Cx43+/- mice. The renal cortex of 5-month-old RenTgCx43+/- mice showed a marked decrease of cell adhesion markers leading to reduced monocyte infiltration and interstitial renal fibrosis compared with their littermates. In addition, functional and histological parameters such as albuminuria and glomerulosclerosis were ameliorated in RenTgCx43+/- mice. Interestingly, treatment with Cx43 antisense produced remarkable improvement of renal function and structure in 1-year-old RenTg mice. Similar results were found in Cx43+/- or wild-type mice treated with Cx43 antisense after obstructive nephropathy. Furthermore, in these mice, Cx43 antisense attenuated E-cadherin downregulation and phosphorylation of the transcription factor Sp1 by the ERK pathway resulting in decreased transcription of type I collagen gene. Interestingly, Cx43-specific blocking peptide inhibited monocyte adhesion in activated endothelium and profibrotic pathways in tubular cells. Cx43 was highly increased in biopsies of patients with CKD. Thus, Cx43 may represent a new therapeutic target against the progression of CKD.
1] INSERM UMR-S1155, Tenon Hospital, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 6, Paris, France.
Ahmed
A
Abed
1] INSERM UMR-S1155, Tenon Hospital, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 6, Paris, France.
Julie
J
Toubas
INSERM UMR-S1155, Tenon Hospital, Paris, France.
Panagiotis
P
Kavvadas
INSERM UMR-S1155, Tenon Hospital, Paris, France.
Florence
F
Authier
INSERM UMR-S1155, Tenon Hospital, Paris, France.
Dominique
D
Cathelin
INSERM UMR-S1155, Tenon Hospital, Paris, France.
Carlo
C
Alfieri
1] INSERM UMR-S1155, Tenon Hospital, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 6, Paris, France [3] Department of Nephrology, Tenon Hospital, Paris, France.
Jean-Jacques
JJ
Boffa
1] INSERM UMR-S1155, Tenon Hospital, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 6, Paris, France [3] Department of Physiology, Saint-Antoine Hospital, Paris, France.
Jean-Claude
JC
Dussaule
1] INSERM UMR-S1155, Tenon Hospital, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 6, Paris, France.
Christos
C
Chatziantoniou
1] INSERM UMR-S1155, Tenon Hospital, Paris, France [2] Sorbonne Universités, UPMC Univ Paris 6, Paris, France.
Christos E
CE
Chadjichristos
D000419:Albuminuria / Q000188:drug therapy / Q000235:genetics; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D024042:Collagen Type I / Q000235:genetics; D018031:Connexin 43 / Q000032:analysis / Q000235:genetics*; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D005355:Fibrosis; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D009000:Monocytes / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic
D015820:Cadherins; D024042:Collagen Type I; D018031:Connexin 43; D016376:Oligonucleotides, Antisense; D016329:Sp1 Transcription Factor