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Mind the gap: connexins and cell–cell communication in the diabetic kidney

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Abstract

Connexins, assembled as a hexameric connexon, form a transmembrane hemichannel that provides a conduit for paracrine signalling of small molecules and ions to regulate the activity and function of adjacent cells. When hemichannels align and associate with similar channels on opposing cells, they form a continuous aqueous pore or gap junction, allowing the direct transmission of metabolic and electrical signals between coupled cells. Regulation of gap junction synthesis and channel activity is critical for cell function, and a number of diseases can be attributed to changes in the expression/function of these important proteins. Diabetic nephropathy is associated with several complex metabolic and inflammatory responses characterised by defects at the molecular, cellular and tissue level. In both type 1 and type 2 diabetes, glycaemic injury of the kidney is the leading cause of end-stage renal failure, a consequence of multiple aetiologies, including increased deposition of extracellular matrix, glomerular hyperfiltration, albuminuria and tubulointerstitial fibrosis. In diabetic nephropathy, loss of connexin mediated cell–cell communication within the nephron may represent an early sign of disease; however, our current knowledge of the role of connexins in the diabetic kidney is sparse. This review highlights recent evidence demonstrating that maintenance of connexin-mediated cell–cell communication could benefit region-specific renal function in diabetic nephropathy and suggests that these proteins should be viewed as a tantalising novel target for therapeutic intervention.

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Abbreviations

α-Sma:

α-Smooth muscle actin

CX:

Connexin

E-cadherin:

Epithelial cadherin

ECM:

Extracellular matrix

EMT:

Epithelial-to-mesenchymal transition

ESRD:

End-stage renal disease

GJIC:

Gap junction intercellular communication

N-cadherin:

Neural cadherin

STZ:

Streptozotocin

ZDF:

Zucker Diabetic Fatty

ZL:

Zucker Lean

ZO-1:

Zonula occludens 1

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Acknowledgements

This work was supported by the generous support of Diabetes UK (BDA:11/0004215 and BDA:12/0004546), an EFSD/Janssen grant and a contribution from the Lincoln Institute of Health.

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The authors declare that there is no duality of interest associated with this manuscript.

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All authors contributed to drafting the manuscript and have approved the final version for publication.

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  1. School of Life Sciences, University of Lincoln, Brayford Pool, Lincoln, LN6 7TS, UK

    Claire E. Hills, Gareth W. Price & Paul E. Squires

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  1. Claire E. Hills
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  2. Gareth W. Price
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Correspondence to Claire E. Hills.

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Hills, C.E., Price, G.W. & Squires, P.E. Mind the gap: connexins and cell–cell communication in the diabetic kidney. Diabetologia 58, 233–241 (2015). https://doi.org/10.1007/s00125-014-3427-1

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