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

2020 ◽  
Vol 13 (653) ◽  
pp. eabc6967 ◽  
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.

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

2019 ◽  
Author(s):  
Roberta Gualdani ◽  
François Seghers ◽  
Xavier Yerna ◽  
Olivier Schakman ◽  
Nicolas Tajeddine ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Ion Channel ◽  
Proximal Tubule ◽  
Mechanical Activation ◽  
Low Molecular Weight ◽  
Systemic Delivery ◽  
Proximal Tubule Cells ◽  
Basolateral Side ◽  
Protein Reabsorption ◽  
Low Molecular Weight Proteins

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.

scholarly journals Megalin is an endocytic receptor for insulin.

1998 ◽  
Vol 9 (10) ◽  
pp. 1759-1766 ◽  
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.

scholarly journals Transcellular Transport of Vitamin B12in LLC-PK1 Renal Proximal Tubule Cells

2001 ◽  
Vol 12 (6) ◽  
pp. 1099-1106 ◽  
Author(s):  
RIKKE NIELSEN ◽  
BOE SANDAHL SØRENSEN ◽  
HENRIK BIRN ◽  
ERIK ILSØ CHRISTENSEN ◽  
EBBA NEXØ
Keyword(s):  
Proximal Tubule ◽  
Vitamin B ◽  
Proximal Tubule Cells ◽  
Transcellular Transport ◽  
Reverse Transcription Pcr ◽  
Affinity Ligand ◽  
Basolateral Side ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells ◽  
High Affinity Ligand

Abstract. The transcobalamin-vitamin B12complex is responsible for the transport of B12from plasma and into the tissues. The complex is filtered in the renal glomeruli and is a high-affinity ligand for the endocytic receptor megalin expressed in the proximal tubule. This study shows by the use of the proximal tubule LLC-PK1 cell line that transcobalamin-B12is internalized by megalin-mediated endocytosis. After endocytosis and accumulation in endosomes, transcobalamin is degraded and the B12molecule is released from the cells in complex with newly synthesized proteins. The release is polarized in such a way that vitamin in the apical medium is bound to proteins with the size of haptocorrin, whereas the B12released at the basolateral side is complexed to two different proteins with the sizes of transcobalamin and haptocorrin. Furthermore, transcobalamin mRNA was identified by reverse transcription-PCR in LLC-PK1 cells and human and pig kidney, whereas haptocorrin mRNA was identified only in LLC-PK1 cells. The results strongly suggest that megalin located in the proximal tubule cells is important for receptor-mediated tubular reabsorption followed by transcellular transport and release of vitamin B12complexed to newly synthesized carrier proteins. This mechanism is likely to play a significant role in the maintenance of B12homeostasis by returning filtered B12to the pool of circulating vitamin.

Nephrotoxicity Testing In Vitro: The Current Situation

1997 ◽  
Vol 25 (5) ◽  
pp. 497-503
Author(s):  
Jean-Paul Morin ◽  
Marc E. De Broe ◽  
Walter Pfaller ◽  
Gabriele Schmuck
Keyword(s):  
Proximal Tubule ◽  
Culture Media ◽  
Task Force ◽  
Primary Cultures ◽  
Phenotypic Expression ◽  
Transepithelial Transport ◽  
Specific Cell ◽  
Proximal Tubule Cells ◽  
Tubule Cells

An ECVAM task force on nephrotoxicity has been established to advise, in particular, on the follow-up to recommendations made in the ECVAM workshop report on nephrotoxicity testing in vitro. Since this workshop was held, in 1994, there have been several improvements in the techniques used. For example, the duration of renal slice viability, and the maintenance of functional activities in slices, have been improved by using dynamic incubation systems with higher oxygen tensions and more-appropriate cell culture media. Highly differentiated primary cultures of pig, human and rabbit proximal tubule cells have been established by using specific cell isolation procedures and/or selective culture media. To date, the most comparable phenotypic expression and transepithelial transport capacities to proximal tubules in vivo have been obtained with primary cultures of rabbit proximal tubule cells which are grown on bicompartmental supports; in this system, transepithelial substrate gradients are generated and the transepithelial transport of both organic anions and cations is highly active. This in vitro system has been selected by ECVAM for further evaluation and prevalidation. Industrial needs in the area of nephrotoxicity testing have been identified, and recommendations are made at the end of this report concerning possible future initiatives.

Inhibition of Copper-Associated Erythrocyte Ghost Membrane Lipid Peroxidation by Hepatic Cytosolic Low Molecular Weight Proteins

1991 ◽  
Vol 19 (3) ◽  
pp. 206-213
Author(s):  
Bruce L. Homer ◽  
Kenneth R. Pierce ◽  
Charles H. Bridges ◽  
James E. Womack ◽  
Blair A. Sowa ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Molecular Weight ◽  
Membrane Lipid ◽  
Erythrocyte Ghost ◽  
Low Molecular Weight ◽  
Membrane Lipid Peroxidation ◽  
Low Molecular Weight Proteins

Effects of TCDD and estradiol-17β on the proliferation and Na+/glucose cotransporter in renal proximal tubule cells

2005 ◽  
Vol 19 (1) ◽  
pp. 21-30 ◽  
Author(s):  
Ho Jae Han ◽  
Min Jin Lim ◽  
Yun Jung Lee ◽  
Eun Jung Kim ◽  
Young Jin Jeon ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells ◽  
Estradiol 17Β
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