Down the kidney tubes: insights into renal proximal tubule drug handling to improve in vitro nephrotoxicity screening

Contains fulltext : 196863.pdf (publisher's version ) (Open Access)Radboud University, 28 november 2018Promotores : Masereeuw, R., Russel, F.G.M. Co-promotor : Wilmer, M.J.G

Kidney-on-a-chip technology for renal proximal tubule tissue reconstruction

The renal proximal tubule epithelium is responsible for active secretion of endogenous and exogenous waste products from the body and simultaneous reabsorption of vital compounds from the glomerular filtrate. The complexity of this transport machinery makes investigation of processes such as tubular drug secretion a continuous challenge for researchers. Currently available renal cell culture models often lack sufficient physiological relevance and reliability. Introducing complex biological culture systems in a 3D microfluidic design improves the physiological relevance of in vitro renal proximal tubule epithelium models. Organ-on-a-chip technology provides a promising alternative, as it allows the reconstruction of a renal tubule structure. These microfluidic systems mimic the in vivo microenvironment including multi-compartmentalization and exposure to fluid shear stress. Increasing data supports that fluid shear stress impacts the phenotype and functionality of proximal tubule cultures, for which we provide an extensive background. In this review, we discuss recent developments of kidney-on-a-chip platforms with current and future applications. The improved proximal tubule functionality using 3D microfluidic systems is placed in perspective of investigating cellular signalling that can elucidate mechanistic aberrations involved in drug-induced kidney toxicity

Therapy with 2 '-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption

Contains fulltext : 214061.pdf (publisher's version ) (Open Access

Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity

Cisplatin is a cytostatic drug used for treatment of solid organ tumors. The main adverse effect is organic cation transporter 2 (OCT2)-mediated nephrotoxicity, observed in 30% of patients. The contribution of other renal drug transporters is elusive. Here, cisplatin-induced toxicity was evaluated in human-derived conditionally immortalized proximal tubule epithelial cells (ciPTEC) expressing renal drug transporters, including OCT2 and organic anion transporters 1 (OAT1) or 3 (OAT3). Parent ciPTEC demonstrated OCT2-dependent cisplatin toxicity (TC50 34 +/- 1 muM after 24-hour exposure), as determined by cell viability. Overexpression of OAT1 and OAT3 resulted in reduced sensitivity to cisplatin (TC50 45 +/- 6 and 64 +/- 11 muM after 24-hour exposure, respectively). This effect was independent of OAT-mediated transport, as the OAT substrates probenecid and diclofenac did not influence cytotoxicity. Decreased cisplatin sensitivity in OAT-expressing cells was associated directly with a trend toward reduced intracellular cisplatin accumulation, explained by reduced OCT2 gene expression and activity. This was evaluated by Vmax of the OCT2-model substrate ASP(+) (23.5 +/- 0.1, 13.1 +/- 0.3, and 21.6 +/- 0.6 minutes(-1) in ciPTEC-parent, ciPTEC-OAT1, and ciPTEC-OAT3, respectively). Although gene expression of cisplatin efflux transporter multidrug and toxin extrusion 1 (MATE1) was 16.2 +/- 0.3-fold upregulated in ciPTEC-OAT1 and 6.1 +/- 0.7-fold in ciPTEC-OAT3, toxicity was unaffected by the MATE substrate pyrimethamine, suggesting that MATE1 does not play a role in the current experimental set-up. In conclusion, OAT expression results in reduced cisplatin sensitivity in renal proximal tubule cells, explained by reduced OCT2-mediated uptake capacity. In vitro drug-induced toxicity studies should consider models that express both OCT and OAT drug transporters

Flow stimulates drug transport in a human kidney proximal tubule-on-a-chip independent of primary cilia

Contains fulltext : 214147.pdf (publisher's version ) (Open Access

Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules

Contains fulltext : 194882.pdf (publisher's version ) (Open Access

Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules

Nephrolog