Research ArticlePhysiology

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

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Science Signaling  13 Oct 2020:
Vol. 13, Issue 653, eabc6967
DOI: 10.1126/scisignal.abc6967

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Endocytosis under pressure

The kidneys filter the blood multiple times a day through structures known as glomeruli, and filtered water, solutes, and proteins such as albumin are reabsorbed by the proximal tubule and returned to the circulation. Kidney damage or disease may result in proteinuria, which can lead to nephropathy if left unchecked. Gualdani et al. found that mechanosensing induced by fluid flow through the proximal tubule activated the cation channel TRPV4 to promote the endocytosis of albumin in tubular epithelial cells and, thus, its retention. Experimental manipulations that increased the permeability of the glomerular filter exacerbated proteinuria in mice lacking TRPV4 globally or specifically in the proximal tubule. Thus, defects in TRPV4-mediated endocytosis may underlie proteinuria, a common symptom of many kidney diseases.

Abstract

Defects in protein reabsorption by the proximal tubule are toxic for epithelial cells in the nephron and may result in nephropathy. In this study, we showed that the ion channel TRPV4 modulated the endocytosis of albumin and low–molecular weight proteins in the proximal tubule. TRPV4 was found at the basolateral side of proximal tubule cells, and its mechanical activation by cell stretching induced Ca2+ entry into the cytosol, which promoted endocytosis. Trpv4−/− mice presented with mild proximal tubule dysfunction under basal conditions. To challenge endocytic function, the permeability of the glomerular filter was altered by systemic delivery of angiotensin II. The proteinuria induced by this treatment was more severe in Trpv4−/− than in Trpv4+/+ mice. Injecting antibodies against the glomerular basement membrane to induce glomerulonephritis is a more pathophysiologically relevant method of impairing glomerular filter permeability. Albuminuria was more severe in mice that lacked TRPV4 specifically in the proximal tubule than in control mice. These results emphasize the importance of TRPV4 in sensing pressure in the proximal tubule in response to variations in the amount of ultrafiltrate and unveil a mechanism that controls protein reabsorption.

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