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

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.

Multiubiquitination of TRPV4 reduces channel activity independent of surface localization

“…1 A ) and a doublet in MDCK cells and choroid plexus tissue ( Fig. 1 , B and C ) consistent with previous studies ( 39 , 44 , 45 , 46 , 47 ).

Figure 1 TRPV4 is monoubiquitinated/multiubiquitinated.

…”

“…Our data showed a single TRPV4 band in 50B11 cells (Fig 1A) and a doublet in MDCK cells and choroid plexus tissue (Fig. 1B, C) consistent with previous studies (39,(44)(45)(46)(47).…”

Albumin Expands Albumin Reabsorption Capacity in Proximal Tubule Epithelial Cells through a Positive Feedback Loop between AKT and Megalin

“…The authors correlated this effect to explain how changes in the glomerular flow rate could be translated to changes in PT function. Additionally, cell stretching mechanical activation was also suggested to enhance protein reabsorption by PT cells [ 20 ]. Here, we added a new piece to this puzzle showing that acute changes in luminal albumin concentration under physiologic conditions increased albumin endocytosis.…”

Thermosensitive receptors in neural stem cells link stress-induced hyperthermia to impaired neurogenesis via microglial engulfment

“…Nestin-CreER T2 mice were initially purchased from The Jackson Laboratory (JAX stock #016261) ( 50 ). RCL-tdTomato (JAX stock #007908) and floxed- Trpv4 ( Trpv4 fl/fl ) mice were described previously ( 51 ). To knock out TRPV4 and express tdTomato specifically in NSCs, RCL-tdTomato and Trpv4 fl/fl mice were crossed with Nestin-CreER T2 mice to generate Nestin-CreER T2 ::RCL-tdTomato::Trpv4 fl/fl mice.…”