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

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 th...

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Bibliographic Details
Published in:Science signaling 2020-10, Vol.13 (653)
Main Authors: Gualdani, Roberta, Seghers, François, Yerna, Xavier, Schakman, Olivier, Tajeddine, Nicolas, Achouri, Younès, Tissir, Fadel, Devuyst, Olivier, Gailly, Philippe
Format: Article
Language:English
Subjects:
Activation
Albumin
Albumins
Angiotensin
Angiotensin II
Antibodies
Calcium influx
Calcium ions
Cell activation
Cytosol
Defects
Endocytosis
Epithelial cells
Fluid dynamics
Fluid flow
Glomerulonephritis
Ion channels
Kidney diseases
Kidneys
Molecular weight
Nephropathy
Permeability
Proteins
Proteinuria
Reabsorption
Sodium
Solutes
Water purification
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Summary: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 Ca entry into the cytosol, which promoted endocytosis. 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 than in 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.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.abc6967