Targeting connexin 43 protects against the progression of experimental chronic kidney disease in mice

• Published in: Kidney international Vol. 86; no. 4; pp. 768 - 779
• Main Authors: Abed, Ahmed, Toubas, Julie, Kavvadas, Panagiotis, Authier, Florence, Cathelin, Dominique, Alfieri, Carlo, Boffa, Jean-Jacques, Dussaule, Jean-Claude, Chatziantoniou, Christos, Chadjichristos, Christos E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2014; Elsevier Limited; Nature Publishing Group
• Subjects: Albuminuria - drug therapy; Albuminuria - genetics; Animals; Cadherins - metabolism; Cell Adhesion; chronic kidney disease; Collagen Type I - genetics; Connexin 43 - analysis; Connexin 43 - genetics; Disease Progression; Down-Regulation - drug effects; Fibrosis; Glomerulosclerosis, Focal Segmental - drug therapy; Glomerulosclerosis, Focal Segmental - genetics; Human health and pathology; Humans; inflammation; Life Sciences; MAP Kinase Signaling System; Mice; Monocytes - physiology; Oligonucleotides, Antisense - pharmacology; Oligonucleotides, Antisense - therapeutic use; Phosphorylation - drug effects; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - pathology; Sp1 Transcription Factor - metabolism; Transcription, Genetic; inflammation; chronic kidney disease; fibrosis
• ISSN: 0085-2538; 1523-1755; 1523-1755
• DOI: 10.1038/ki.2014.108

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.