Connexin‐mediated cell communication in the kidney, a potential therapeutic target for future intervention of diabetic kidney disease?: Joan Mott Prize Lecture

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.