Mechanical activation of TRPV4 channels controls albumin reabsorption by proximal tubule cells

The proximal tubule (PT) mediates the endocytosis of essential substances filtered through the glomerulus, including albumin and a large variety of low molecular weight proteins that would otherwise be lost in urine. Variations in the amount of ultrafiltrate delivered to the PT modulate protein endocytosis. Here we show that TRPV4 ion channel is expressed at the basolateral side of PT cells. Mechanical activation of TRPV4 by cell stretching induces an entry of Ca 2+ into the cytosol, which promotes endocytosis. Trpv4 −/- mice present only a mild PT dysfunction in basal conditions but they exhibit a much more severe proteinuria than Trpv4 +/+ mice when the permeability of glomerular filter is altered by systemic delivery of angiotensin II or antibodies against the glomerular basement membrane. These results emphasize the importance of TRPV4 channel in PT pressure sensing and provide insights into the mechanisms controlling protein reabsorption and potential targets for treating tubular proteinuria. Summary The proximal tubule (PT) mediates the endocytosis of albumin and low molecular weight proteins. Gualdani et al. report that variations in the amount of ultrafiltrate delivered to the PT activate TRPV4 ion channel expressed at the basolateral side of PT cells, which modulates protein endocytosis.