Abstract
Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention.
Highlights
Ketamine is a tranquilliser that has found use as an NMDA receptor antagonist in the treatment of human bipolar disorders [1]
We examine potential cellular mechanisms orchestrating these changes and utilise high resolution Atomic Force Microscopy (AFM)-single-cell force spectroscopy to assess the functional consequence of cell-cell tethering in Ketamine-treated cells exhibiting a loss in cadherin expression
Cells stimulated for 24 and 48 hrs with Ketamine (0.1–1 mg/ mL) under serum-free conditions were assessed for cell viability by MTT uptake
Summary
Ketamine is a tranquilliser that has found use as an NMDA receptor antagonist in the treatment of human bipolar disorders [1]. In 2006 the UK government made Ketamine a class C drug. Possessing mild hallucinogenic properties, Ketamine is rapidly replacing heroin and methamphetamine as the recreational drug of choice [2]. First documented in 2007, Ketamine has been shown to injure the bladder, causing ulcers (wounds) and fibrosis (stiffening of the bladder walls and shrinkage) [4]. Patients present with multiple symptoms including incontinence, bleeding, overactive bladder and bladder shrinkage, as well as damage to both the kidneys and the ureter [5]. Despite the growing presentation of these complications, there is an acute lack of understanding for the mechanisms that underlie the pathophysiological of Ketamine, and we urgently need to investigate how this mild hallucinogenic drug scars bladder and renal tissue to impair function [6]
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