Expression of the gap junction protein connexin 43 (Cx43) is upregulated in chronic kidney disease (CKD). Kavvadas et al. further examined the relationship between Cx43 and kidney injury: “Our goal was to test the efficiency of Cx43 blockade in a severe model of CKD that corresponds to the human pathology and to try to identify the molecular mechanisms of Cx43 actions,” says Panagiotis Kavvadas.

The researchers examined the effects of downregulating Cx43 expression in vivo using genetic and pharmacogenetic approaches in a mouse model of severe glomerulonephritis (GN) induced with nephrotoxic serum. The adverse effects of nephrotoxic serum on renal structure, function, inflammation and fibrosis were ameliorated in mice with a heterozygous deletion of Cx43 compared with wild-type mice. Importantly, reducing Cx43 expression in wild-type mice using antisense oligonucleotides delayed the development of nephrotoxic serum-induced GN.

The deleterious role of Cx43 in GN may [be partly] due to a proapoptotic role in … the podocyte

As Cx43 is highly expressed in injured podocytes, the investigators studied the effects of modulating Cx43 function in vitro in a podocyte cell line. Upregulation of Cx43 expression (induced by TGFβ treatment) in these cells resulted in podocyte dedifferentiation and apoptosis, which was blocked by pretreatment with Cx43 blocking peptides. Blocking purinergic signalling mimicked the results of Cx43 blockade, suggesting that the effects of Cx43 on podocytes may be mediated through this pathway. “The deleterious role of Cx43 in GN may not be exclusively due to the pro-inflammatory capacity of Cx43 but may also be due to a pro-apoptotic role in the main cellular target of the disease, the podocyte,” suggests Kavvadas. “Combined therapies involving Cx43 targeting could provide an alternative therapeutic strategy to treat CKD.”