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Decreased Expression of Connexin 43 Blunts the Progression of Experimental GN.

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 experimental GN. Notably, 2 weeks after the induction of GN with nephrotoxic serum, mice with 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.

SUBMITTER: Kavvadas P

PROVIDER: S-EPMC5619962 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Connexins (C×s) are a family of transmembrane proteins that form hemichannels and gap junctions (GJs) on the cell membranes, and transfer small signaling molecules between the cytoplasm and extracellular space and between connecting cells, respectively. Among C×s, suppressing C×43 expression or function promotes skin wound closure and granulation tissue formation, and may alleviate scarring, but the mechanisms are not well understood. Oral mucosal gingiva is characterized by faster wound closure and scarless wound healing outcome as compared to skin wounds. Therefore, we hypothesized that C×43 function is down regulated during human gingival wound healing, which in fibroblasts promotes expression of genes conducive for fast and scarless wound healing. Cultured gingival fibroblasts expressed C×43 as their major connexin. Immunostaining of unwounded human gingiva showed that C×43 was abundantly present in the epithelium, and in connective tissue formed large C×43 plaques in fibroblasts. At the early stages of wound healing, C×43 was strongly down regulated in wound epithelial cells and fibroblasts, returning to the level of normal tissue by day 60 post-wounding. Blocking of C×43 function by C×43 mimetic peptide Gap27 suppressed GJ-mediated dye transfer, promoted migration, and caused significant changes in the expression of wound healing-associated genes in gingival fibroblasts. In particular, out of 54 genes analyzed, several MMPs and TGF-β1, involved in regulation of inflammation and extracellular matrix (ECM) turnover, and VEGF-A, involved in angiogenesis, were significantly upregulated while pro-fibrotic ECM molecules, including Collagen type I, and cell contractility-related molecules were significantly down regulated. These responses involved MAPK, GSK3α/β and TGF-β signaling pathways, and AP1 and SP1 transcription factors. Thus, suppressed function of C×43 in fibroblasts promotes their migration, and regulates expression of wound healing-associated genes via AP1, SP1, MAPK, GSK3α/β and TGF-β signaling pathways, and may promote fast and scarless wound healing in human gingiva.

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Decreased Expression of Connexin 43 Blunts the Progression of Experimental GN.

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