Flow stimulated endocytosis in the proximal tubule

Abstract

Purpose of review The proximal tubule (PT) plays a critical role in the reabsorption of ions, solutes and low molecular weight proteins from the glomerular filtrate. Although the PT has long been known to acutely modulate ion reabsorption in response to changes in flow rates of the glomerular filtrate, it has only recently been discovered that PT cells can similarly adjust endocytic capacity in response to flow. This review synthesizes our current understanding of mechanosensitive regulation of endocytic capacity in PT epithelia and highlights areas of opportunity for future investigations. Recent findings Recent studies have reported that the endocytic capacity of PT cells is dramatically increased upon exposure to flow and the accompanying fluid shear stress (FSS). Modulation of this pathway is dependent on increases in intracellular calcium [Ca2+]i initiated by bending of the primary cilium, and also requires purinergic receptor activation that is mediated by release of extracellular ATP. This article summarizes what is currently known about the signaling cascade that transduces changes in flow into alterations in endocytosis. We discuss the implications of this newly described regulatory pathway with respect to our understanding of protein retrieval by the kidney under normal conditions, and in diseases that present with low molecular weight proteinuria. Summary Primary cilia act as mechanotransducers that modulate apical endocytic capacity in PT cells in response to changes in fluid shear stress.

PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress

“…We therefore propose that class 3 and class 2 PI3kinases are involved in different kinds of autophagic response. Thus, it can be postulated that cellular adaptation to shear stress mobilizes PI3KC2αdependent PI3P synthesis without depending on VPS34, which in turn is available for endosomal trafficking regulation, as a putative consequence of previously reported increase in shear stress-induced endocytosis 39,40 , as well for autophagic response to other stimuli.…”

Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules

“…1c, RPTEC formed a tubular structure with cells lining the ECM (curved part of the tubule) and the walls of the channel, thus having an open, perfused lumen. Confluent tubules formed tight junctions as visualized by the zona-occludence 1 tight junction (ZO-1) expression (15), and display primary cilia visualized by acetylated tubulin staining (16). A single cilium per cell was observed, located at the apical side of the cell layer pointing towards the lumen of the tubule (Fig.…”

Cdc42 activation couples fluid shear stress to apical endocytosis in proximal tubule cells

“…This mechanism prevents loss of solute after increases in GFR and maintains the adequate distal delivery of sodium and fluid when GFR is reduced. PT cells respond to mechanical forces, including FSS, with immediate downstream signal transduction events as well as long-term adaptation mechanisms that enable them to fine-tune their cytoskeleton structure, intercellular junctions, and cell-substratum interactions to adjust to the mechanical challenge (Weinbaum et al 2010;Raghavan and Weisz 2015).…”