Human proximal tubule epithelial cells cultured on hollow fibers: living membranes that actively transport organic cations

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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.

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Chronic kidney disease as cause of cardiovascular morbidity and mortality.

R Vanholder, Z Massy, A Argilés … (2005)

To make an evidence-based evaluation of the relationship between kidney failure and cardiovascular risk, we reviewed the literature obtained from a PubMed search using pre-defined keywords related to both conditions and covering 18 years (1986 until end 2003). Eighty-five publications, covering 552 258 subjects, are summarized. All but three studies support a link between kidney dysfunction and cardiovascular risk. More importantly, the association is observed very early during the evolution of renal failure: an accelerated cardiovascular risk appears at varying glomerular filtration rate (GFR) cut-off values, which were >/=60 ml/min in at least 20 studies. Many studies lacked a clear definition of cardiovascular disease and/or used a single determination of serum creatinine or GFR as an index of kidney function, which is not necessarily corresponding to well-defined chronic kidney disease. In six studies, however, chronic kidney dysfunction and cardiovascular disease were well defined and the results of these confirm the impact of kidney dysfunction. It is concluded that there is an undeniable link between kidney dysfunction and cardiovascular risk and that the presence of even subtle kidney dysfunction should be considered as one of the conditions necessitating intensive prevention of this cardiovascular risk.

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Recellularization of well-preserved acellular kidney scaffold using embryonic stem cells.

Barbara Bonandrini, Marina Figliuzzi, Evangelia Papadimou … (2014)

For chronic kidney diseases, there is little chance that the vast majority of world's population will have access to renal replacement therapy with dialysis or transplantation. Tissue engineering would help to address this shortcoming by regeneration of damaged kidney using naturally occurring scaffolds seeded with precursor renal cells. The aims of the present study were to optimize the production of three-dimensional (3D) rat whole-kidney scaffolds by shortening the duration of organ decellularization process using detergents that avoid nonionic compounds, to investigate integrity of extracellular matrix (ECM) structure and to enhance the efficacy of scaffold cellularization using physiological perfusion method. Intact rat kidneys were successfully decellularized after 17 h perfusion with sodium dodecyl sulfate. The whole-kidney scaffolds preserved the 3D architecture of blood vessels, glomeruli, and tubuli as shown by transmission and scanning electron microscopy. Micro-computerized tomography (micro-CT) scan confirmed integrity, patency, and connection of the vascular network. Collagen IV, laminin, and fibronectin staining of decellularized scaffolds were similar to those of native kidney tissues. After infusion of whole-kidney scaffolds with murine embryonic stem (mES) cells through the renal artery, and pressure-controlled perfusion with recirculating cell medium for 24 and 72 h, seeded cells were almost completely retained into the organ and uniformly distributed in the vascular network and glomerular capillaries without major signs of apoptosis. Occasionally, mES cells reached peritubular capillary and tubular compartment. We observed the loss of cell pluripotency and the start of differentiation toward meso-endodermal lineage. Our findings indicate that, with the proposed optimized protocol, rat kidneys can be efficiently decellularized to produce renal ECM scaffolds in a relatively short time, and rapid recellularization of vascular structures and glomeruli. This experimental setup may open the possibility to obtain differentiation of stem cells with long lasting in vitro perfusion.

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The kidney and uremic toxin removal: glomerulus or tubule?

Rosalinde Masereeuw, Henricus Mutsaers, Takafumi Toyohara … (2014)

Chronic kidney disease (CKD) is a condition that affects approximately 10% of the adult population in developed countries. In patients with CKD adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also known as uremic toxins, are a heterogeneous group of organic compounds, many are too large to be filtered (middle molecules) or are protein-bound. Tubular secretion shifts the binding and allows for active secretion of such solutes. To mediate urinary solute excretion, renal proximal tubules are equipped with a range of transporters that cooperate in basolateral uptake and luminal excretion. These putative uremic toxins are poorly filtered across dialysis membranes because they are protein bound and current dialysis therapy does not correct the full spectrum of uremic toxicity. Residual renal function, which may represent an important contribution of solutes secreted by the proximal tubule rather than unreabsorbed filtrate, is an important predictor of survival of CKD patients. Many of the transporters that mediate the renal excretion of uremic retention solutes were first recognized as mediators of drug trafficking and drug-drug interactions, and a considerable amount of literature concerning the actions of these transporters antedates the recognition of their importance in the proximal renal tubular transport of uremic retention solutes. These transporters include members belonging to the organic cation/anion/zwitterion solute carrier family, such as the organic anion transporters (OAT)1, OAT3, and OATP4C1, and to the adenosine triphosphate binding cassette superfamily of transmembrane transporters, including the multidrug resistance proteins and breast cancer resistance protein. This article draws on this body of information to describe the renal tubular clearance mechanisms for uremic toxins, as well as the intracellular events associated with their accumulation, involving activation of the aryl hydrocarbon receptor, disturbance of mitochondrial functioning, and competition with metabolizing enzymes.

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Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 16 November 2015

Publication date Collection: 2015

Volume: 5

Electronic Location Identifier: 16702

Affiliations

[1 ]Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands

[2 ]Department of Physiology, Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands

[3 ]Department of Pediatrics, Radboud university medical center , Nijmegen, The Netherlands

[4 ]Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , The Netherlands

[5 ]Department of Biochemistry, Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands

[6 ]Department of Cell Biology, Radboud university medical center, Radboud Institute for Molecular Life Sciences , Nijmegen, The Netherlands.

[7 ]Department of Nephrology, Radboud university medical center , Nijmegen, The Netherlands.

[8 ]Department of Pediatric Nephrology & Growth and Regeneration, Catholic University Leuven , Leuven, Belgium.

[9 ]Div. Pharmacology, Department of Pharmaceutical Sciences, Utrecht University , The Netherlands.

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[a ] r.masereeuw@ 123456uu.nl

Article

Publisher Item ID: srep16702

DOI: 10.1038/srep16702

PMC ID: 4644946

PubMed ID: 26567716

SO-VID: 229641c5-5dec-4789-95dd-c06db8e39fbb

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Human proximal tubule epithelial cells cultured on hollow fibers: living membranes that actively transport organic cations

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Universal stem cells

Most cited references 30

Chronic kidney disease as cause of cardiovascular morbidity and mortality.

Recellularization of well-preserved acellular kidney scaffold using embryonic stem cells.

The kidney and uremic toxin removal: glomerulus or tubule?

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