Decreased expression of connexin 43 blunts the progression of experimental GN

Panagiotis Kavvadas, Ahmed Abed, Coralie Poulain, Florence Authier, Lise Paule Labéjof, Amelie Calmont, Carlo Afieri, Niki Prakoura, Jean Claude Dussaule, Christos Chatziantoniou, Christos E. Chadjichristos

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Abstract

GN refers to a variety of renal pathologies that often progress to ESRD, but the molecular mechanisms underlying this progression remain incompletely characterized. Here, we determined whether dysregulated expression of the gap junction protein connexin 43, which has been observed in the progression of renal disease, contributes to GN progression. Immunostaining revealed de novo expression of connexin 43 in damaged glomeruli in patients with glomerular diseases as well as in mice after induction of experimentalGN. Notably, 2weeks after the induction ofGNwith nephrotoxic serum, micewith a heterozygous deletion of the connexin 43 gene (connexin 43+/-) had proteinuria, BUN, and serum creatinine levels significantly lower than those of wild-type animals. Additionally, the connexin 43+/- mice showed less crescent formation, tubular dilation, monocyte infiltration, and interstitial renal fibrosis. Treatment of cultured podocytes with connexin 43-specific blocking peptides attenuated TGF-β-induced cytoskeletal and morphologic changes and apoptosis as did treatment with the purinergic blocker suramin. Finally, therapeutic treatment of GN mice with connexin 43-specific antisense oligodeoxynucleotide improved functional and structural renal parameters. These findings suggest that crosstalk between connexin 43 and purinergic signaling contributes to podocyte damage in GN. Given that this protein is highly induced in individuals with glomerular diseases, connexin 43 may be a novel target for therapeutic treatment of GN.

Original languageEnglish
Pages (from-to)2915-2930
Number of pages16
JournalJournal of the American Society of Nephrology
Volume28
Issue number10
DOIs
Publication statusPublished - Oct 1 2017

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ASJC Scopus subject areas

  • Nephrology

Cite this

Kavvadas, P., Abed, A., Poulain, C., Authier, F., Labéjof, L. P., Calmont, A., Afieri, C., Prakoura, N., Dussaule, J. C., Chatziantoniou, C., & Chadjichristos, C. E. (2017). Decreased expression of connexin 43 blunts the progression of experimental GN. Journal of the American Society of Nephrology, 28(10), 2915-2930. https://doi.org/10.1681/ASN.2016111211