Abstract
Cisplatin is a potent anti-cancer drug that has been widely used in the treatment of various cancers; however, cisplatin administration results in severe nephrotoxicity and impedes its clinical applications. In this study, we showed that honokiol, a polyphenol constituent extracted from Magnolia officinalis exhibited a short-term protective effect against cisplatin-induced damages in renal epithelial cells in vitro. The protective effects of honokiol were resulted from the combination of (1) reduced cellular oxidative stress ranging from 53 to 32% reduction during a 24-h incubation, (2) the maintenance of cellular antioxidant capacity and (3) the stabilization of cytoskeletal structure of the kidney epithelial cells. By promoting the polymerization of actin (1.6-fold increase) and tubulin (1.8-fold increase) cytoskeleton, honokiol not only maintained epithelial cell morphology, but also stabilized cellular localizations of tight junction protein Occludin and adhesion junction protein E-Cadherin. With stabilized junction protein complexes and structural polymerized cytoskeleton network, honokiol preserved epithelial cell polarity and morphology and thus reduced cisplatin-induced cell disruption and damages. Our data demonstrated for the first time that honokiol could counteract with cisplatin-induced damages in renal epithelial cells in vitro, future in vivo studies would further validate the potential clinical application of honokiol in cisplatin-based cancer treatments with reduced nephrotoxicity.
Highlights
The kidney is an important organ responsible for waste elimination, electrolyte balance and erythropoietin production (Brown et al, 2012)
We detected no significant changes on protein expression level for both E-Cadherin and Occludin upon cisplatin or HNK treatments (Figure 1B); when cells were grown in polarized 2D Transwell R system, an apparent redistribution of both proteins was noted (Figure 1C)
The morphology of the epithelial cells relies on structural organization of polymerized cytoskeleton, we showed in Figure 3A that when cells treated with latrunculin B for 24 h, a compound that prevents the polymerization of actin, a minimal amount of F-actin was detected; remnants of actin aggregates were observed at the edges of the cells; when cells were allowed to recover in a complete DMEM for 4 h after maximum de-polymerization with latrunculin B, the complexity of polymerized actin network and the stress fibers were observed (Figure 3B)
Summary
The kidney is an important organ responsible for waste elimination, electrolyte balance and erythropoietin production (Brown et al, 2012). Kidney consists of various tubule structure formed by a single layer of epithelial cells that their apical membranes face toward the lumen where urine/water, endogenous waste and hormones are deposited to or secreted into (Brown et al, 2012), and their lateral membranes of adjacent renal epithelial cells are connected by junction protein complexes (Giepmans and van Ijzendoorn, 2009). To maintain this spatial segregation and orientation, epithelial cells must establish their cellular polarity. Alterations of kidney epithelial cell polarity have been reported in various pathological processes (Fish and Molitoris, 1994) and loss of cell polarity in kidney tubules upon the occurrence of AKI and CKD results in disruption of basic kidney tubular structure and defects of vital physiological functions (Thadhani et al, 1996)
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