Connexin‐mediated cell communication in the kidney: A potential therapeutic target for future intervention of diabetic kidney disease?

Abstract

The ability of cells to communicate and synchronise their activity is essential for the maintenance of tissue structure, integrity and function. A family of membrane-bound proteins called connexins are largely responsible for mediating the local transfer of information between cells. Assembled in the cell membrane as a hexameric connexon, they either function as a conduit for paracrine signalling, forming a transmembrane hemi-channel, or, if aligned with connexons on neighbouring cells, form a continuous aqueous pore or gap junction, which allows for the direct transmission of metabolic and electrical signals. Regulation of connexin synthesis and activity is critical to cellular function, and a number of diseases are attributed to changes in the expression and/or function of these important proteins. A link between hyperglycaemia, connexin expression, altered nucleotide concentrations and impaired function highlights a potential role for connexin-mediated cell communication in complications of diabetes. In the diabetic kidney, glycaemic injury is the leading cause of end-stage renal failure, reflecting multiple aetiologies including glomerular hyperfiltration, albuminuria, increased deposition of extracellular matrix and tubulointerstitial fibrosis.Loss of connexin-mediated cell-to-cell communication in diabetic nephropathy may represent an early sign of disease progression, but our understanding of the process remains severely limited. This review focuses on recent evidence demonstrating that glucose-evoked changes in connexin-mediated cell communication and associated purinergic signalling may contribute to the pathogenesis of kidney disease in diabetes, highlighting the tantalising potential of targeting these proteins as a novel therapeutic intervention.

Blocking Connexin-43 mediated hemichannel activity protects against early tubular injury in experimental chronic kidney disease

“…Hyperglycemia and downstream changes in connexin expression are critical in the development and progression of secondary micro-vascular complications, [12][13][14][15] with glucose decreasing gap junction conductance and disrupting cellular homeostasis in a variety of cell types [16][17][18][19]. Evidence that connexin expression is linked to renal damage in CKD [9,11,12,[20][21][22][23][24], suggests that they represent a viable therapeutic target for treatment of the disease. Recent studies have confirmed elevated levels of predominant isoform Cx43, in human and rodent models of early renal disease [20,21] whilst the Cx43 +/− unilateral ureteral obstruction (UUO) mouse demonstrates reduced collagen deposition and macrophage infiltration [24].…”

Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes

“…Connexin hemichannel blockers represent a promising future therapeutic option in the treatment of nephropathy and retinopathy. Research to date is persuasive and highlights promising beneficial effects of Cx43 inhibition on inflammation, tissue integrity and fibrosis [ 180 , 201 , 202 ]. However, the field requires further research to determine the effectiveness and efficacy of drugs and the long-term benefits.…”

TNF-α Plus IL-1β Induces Opposite Regulation of Cx43 Hemichannels and Gap Junctions in Mesangial Cells through a RhoA/ROCK-Dependent Pathway

“…Intercellular communication in the kidney occurs directly via the cytoplasm of adjacent cells connected through GJs, and by paracrine signals released via large-pore channels, such as HCs, pannexons and P2X 7 Rs [ 72 ]. The release of ATP via HCs has multiple functions in the kidney, including regulating renal blood flow, glomerular filtration rate, and renal tubular transport [ 73 ].…”

“…The release of ATP via HCs has multiple functions in the kidney, including regulating renal blood flow, glomerular filtration rate, and renal tubular transport [ 73 ]. However, the HC-mediated release of ATP and further activation of P2 × 7 Rs have been linked to inflammation and fibrosis [ 72 , 74 ]. Multiple studies argue that proinflammatory cytokines may contribute to a chronic activation of endothelial cells, and thereby, a long-term production of key “danger” signals, such as ATP [ 20 , 75 , 76 , 77 ].…”