20 August 2018

Tom Nijenhuis, theme Renal disorders, and colleagues elucidated a novel mechanism that links activity of the calcium-conducting ion channel TRPC6 to structural injury of the kidney filter epithelial cell, via the calcium-dependent protease calpain-1.

Their findings were recently published in the Journal of the American Society of Nephrology. Elucidation of calpain-1 as the long sought-after hub between TRPC6 and kidney injury demonstrates TRPC6 and/or calpain could be future therapeutic treatment targets in kidney disease.

The hallmark of diseases inducing kidney filter injury, such as Focal Segmental Glomerulosclerosis (FSGS), is injury to the renal filter epithelial cell (podocyte), resulting in urinary protein loss and, eventually, kidney failure. The research group at the Nephrology Research Laboratory, Department of Nephrology, had previously shown that overactivity or overexpression of the Transient Receptor Potential channel C6 in the podocyte is associated with podocyte injury and proteinuria, and that inhibiting signaling pathways at the level of TRPC6 is beneficial in vitro as well as in vivo. The researchers showed that e.g. sildenafil (better known as Viagra) regulated podocyte TRPC6 expression and reduced podocyte injury and proteinuria in a previous publication. However, the molecular mechanism linking the TRPC6 channel to podocyte injury, which is characterized by deleterious calcineurin-NFAT signaling and loss of podocyte structural and cytoskeletal proteins, had remained largely elusive.

In their recent publication, the research group showed that stimulation of TRPC6-dependent calcium influx in cultured podocytes increased activity of calpain-1, a calcium-dependent protease. Calpain-1 in turn increased calcineurin activity and reduced expression of the calpain target Talin-1, which links the actin cytoskeleton to integrins and is critical for podocyte cytoskeletal stability, while knockdown or inhibition of TRPC6 or calpain-1 prevented these effects. Compared with kidneys of healthy controls, kidneys of FSGS patients showed increased kidney filter TRPC6 expression, increased calpain and calcineurin activity, and reduced Talin-1 expression. In a rat model of human FSGS,  increased kidney filter and urinary calpain activity was also associated with reduced Talin-1 abundance, enhanced calcineurin activity, and proteinuria. Treatment with the calpain inhibitor calpeptin prevented these effects, demonstrating the putative therapeutic effect of inhibiting this pathogenic mechanism in patients with kidney filter injury.

Tom Nijenhuis
Theme Renal disorders

 

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