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

AbstractThe 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 Ca2+ 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.SummaryThe 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.

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

Science Signaling ◽

10.1126/scisignal.abc6967 ◽

2020 ◽

Vol 13 (653) ◽

pp. eabc6967 ◽

Cited By ~ 1

Author(s):

Roberta Gualdani ◽

François Seghers ◽

Xavier Yerna ◽

Olivier Schakman ◽

Nicolas Tajeddine ◽

...

Keyword(s):

Molecular Weight ◽

Proximal Tubule ◽

Mechanical Activation ◽

Low Molecular Weight ◽

Systemic Delivery ◽

Proximal Tubule Cells ◽

Basolateral Side ◽

Protein Reabsorption ◽

Tubule Cells ◽

Low Molecular Weight Proteins

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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Megalin is an endocytic receptor for insulin.

Journal of the American Society of Nephrology ◽

10.1681/asn.v9101759 ◽

1998 ◽

Vol 9 (10) ◽

pp. 1759-1766 ◽

Cited By ~ 5

Author(s):

R A Orlando ◽

K Rader ◽

F Authier ◽

H Yamazaki ◽

B I Posner ◽

...

Keyword(s):

Molecular Weight ◽

Proximal Tubule ◽

Binding Site ◽

Low Molecular Weight ◽

Apical Surface ◽

Coated Pits ◽

Major Pathway ◽

Proximal Tubule Cells ◽

Glomerular Filtrate ◽

Tubule Cells

Renal clearance is a major pathway for regulating the levels of insulin and other low molecular weight polypeptide hormones in the systemic circulation. Previous studies have shown that the reabsorption of insulin from the glomerular filtrate occurs by binding to as yet unidentified sites on the luminal surface of proximal tubule cells followed by endocytosis and degradation in lysosomes. In this study, an insulin binding site was identified in renal microvillar membranes by chemical cross-linking procedures. By immunoprecipitation it was demonstrated that this binding site is megalin, the large multiligand binding endocytic receptor that is abundantly expressed in clathrin-coated pits on the apical surface of proximal tubule cells. Moreover, using cytochemical procedures, it was also shown that megalin is able to internalize insulin into endocytic vesicles. In ligand blotting assays, megalin also bound several other low molecular weight polypeptides, including beta2-microglobulin, epidermal growth factor, prolactin, lysozyme, and cytochrome c. These data suggest that megalin may play a significant role as a renal reabsorption receptor for the uptake of insulin and other low molecular weight polypeptides from the glomerular filtrate.

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