Abstract
The bioartificial kidney (BAK) aims at improving dialysis by developing ‘living membranes’ for cells-aided removal of uremic metabolites. Here, unique human conditionally immortalized proximal tubule epithelial cell (ciPTEC) monolayers were cultured on biofunctionalized MicroPES (polyethersulfone) hollow fiber membranes (HFM) and functionally tested using microfluidics. Tight monolayer formation was demonstrated by abundant zonula occludens-1 (ZO-1) protein expression along the tight junctions of matured ciPTEC on HFM. A clear barrier function of the monolayer was confirmed by limited diffusion of FITC-inulin. The activity of the organic cation transporter 2 (OCT2) in ciPTEC was evaluated in real-time using a perfusion system by confocal microscopy using 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP+) as a fluorescent substrate. Initial ASP+ uptake was inhibited by a cationic uremic metabolites mixture and by the histamine H2-receptor antagonist, cimetidine. In conclusion, a ‘living membrane’ of renal epithelial cells on MicroPES HFM with demonstrated active organic cation transport was successfully established as a first step in BAK engineering.
Highlights
Metabolic environment as well as drug disposition in the kidney[2,3]
The MicroPES membranes used in this study are hydrophilized fibers used predominantly for plasma separation and have rather large pores allowing the transport of proteins including bovine serum albumin (BSA) and immunoglobulin G (IgG)
The native extracellular matrix (ECM) is a dynamic network consisting of various types of collagen, glycosaminoglycans, laminin and fibronectin connected to integrins present in the plasma membrane
Summary
Metabolic environment as well as drug disposition in the kidney[2,3]. The accumulation of uremic metabolites (i.e. uremic toxins) in the human body may contribute to further progression of renal disease and the association of chronic kidney disease with cardiovascular morbidity[4,5,6]. The surface of MicroPES HFM was functionalized via a double coating to enable tight homogeneous cell monolayer formation. The membrane surface and cross sections of uncoated and coated HFM in the absence of cells were investigated using SEM (Fig. 1A,B).
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