MicroRNA (miRNA) functions in the pathogenesis of major neurodegenerative diseases such as Alzheimer's disease (AD) are only beginning to emerge. We have observed significantly elevated levels of a specific miRNA, miR-26b, in the defined pathological areas of human postmortem brains, starting from early stages of AD (Braak III). Ectopic overexpression of miR-26b in rat primary postmitotic neurons led to the DNA replication and aberrant cell cycle entry (CCE) and, in parallel, increased tau-phosphorylation, which culminated in the apoptotic cell death of neurons. Similar tau hyperphosphorylation and CCE are typical features of neurons in pre-AD brains. Sequence-specific inhibition of miR-26b in culture is neuroprotective against oxidative stress. Retinoblastoma protein (Rb1), a major tumor suppressor, appears as the key direct miR-26b target, which mediates the observed neuronal phenotypes. The downstream signaling involves upregulation of Rb1/E2F cell cycle and pro-apoptotic transcriptional targets, including cyclin E1, and corresponding downregulation of cell cycle inhibitor p27/Kip1. It further leads to nuclear export and activation of Cdk5, a major kinase implicated in tau phosphorylation, regulation of cell cycle, and death in postmitotic neurons. Therefore, upregulation of miR-26b in neurons causes pleiotropic phenotypes that are also observed in AD. Elevated levels of miR-26b may thus contribute to the AD neuronal pathology.

The kidney has an extraordinary ability to maintain stable fractional solute and fluid reabsorption over a wide range of glomerular filtration rates (GFRs). Internalization of filtered low molecular weight proteins, vitamins, hormones, and other small molecules is mediated by the proximal tubule (PT) multiligand receptors megalin and cubilin. Changes in GFR and the accompanying fluid shear stress (FSS) modulate acute changes in PT ion transport. Therefore, we hypothesized that changes in FSS would also modulate protein uptake. We recently discovered that FSS also modulates apical endocytosis in PT cells via a mechanosensitive pathway regulated by primary cilia. FSS caused a rapid and transient increase in intracellular calcium in cells that preceded the endocytic response. Neither the FSS‐stimulated increase in intracellular calcium or apical endocytosis was observed in deciliated cells. Addition of ATP to the medium rescued both responses, suggesting the involvement of purinergic receptors in the signaling cascade. Both basal and FSS‐stimulated endocytosis were inhibited by inhibitors of clathrin and dynamin. Additionally, treatment of PT cells with small molecule inhibitors of Cdc42 or siRNA mediated knockdown of Cdc42 ablated the FSS‐stimulated increase in endocytosis. Similarly knockdown of N‐WASP which participates in nucleation of branched actin filaments prevented the FSS stimulated endocytic response. Our data suggest that exposure of PT cells to FSS enhances apical clathrin‐mediated endocytosis via an actin‐dependent pathway that is modulated by activation of Cdc42, and N‐WASP. Our work defines a novel mechanism that underlies effective protein retrieval by the kidney.

All cells in the body experience external mechanical forces such as shear stress and stretch. These forces are sensed by specialized structures in the cell known as mechanosensors. Cells lining the proximal tubule (PT) of the kidney are continuously exposed to variations in flow rates of the glomerular ultrafiltrate, which manifest as changes in axial shear stress and radial stretch. Studies suggest that these cells respond acutely to variations in flow by modulating their ion transport and endocytic functions to maintain glomerulotubular balance. Conceptually, changes in the axial shear stress in the PT could be sensed by three known structures, namely, the microvilli, the glycocalyx, and primary cilia. The orthogonal component of the force produced by flow exhibits as radial stretch and can cause expansion of the tubule. Forces of stretch are transduced by integrins, by stretch-activated channels, and by cell-cell contacts. This review summarizes our current understanding of flow sensing in PT epithelia, discusses challenges in dissecting the role of individual flow sensors in the mechanosensitive responses, and identifies potential areas of opportunity for new study.

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.