The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity

PLoS One. 2013;8(2):e57016. doi: 10.1371/journal.pone.0057016. Epub 2013 Feb 15.

Abstract

Cisplatin-induced hypomagnesemia is described in humans and rats, but the underlying mechanisms are still unclear. Recent studies have shown that epidermal growth factor (EGF) stimulates Mg(2+) re-absorption in the distal convoluted tubule via the Mg(2+) channel TRPM6. This study investigates the role of TRPM Mg(2+) channels, claudines, and EGF in the Mg(2+) homeostasis in a rat model of cisplatin-induced nephrotoxicity. Wistar rats were given 2.5 mg/kg cisplatin per week for 3 weeks and were euthanized 4 or 9 weeks after the first administration. The cisplatin treatment significantly increased the fractional excretion of Mg(2+). Real-time RT-PCR and/or Western blots were performed to assess the renal expression TRPM6, TRPM7, claudin-16, claudin-19, EGF, EGF receptor (EGFR) and EGFR-pathway components. The renal mRNA expression of TRPM6 and EGF showed a significant decrease after cisplatin treatment, while the TRPM7, claudin-16 and EGFR expressions remained stable. The claudin-19 mRNA expression was significantly upregulated after cisplatin treatment. Western blotting confirmed the mRNA expression data for the claudins, but an showed upregulation of EGFR only at week 9. The role of the EGFR pathway, involving Pi3-AKT-Rac1, in cisplatin-induced nephropathy, could not be substantiated in further detail. This study shows that cisplatin treatment results in EGF and TRPM6 downregulation in the rat kidney, causing renal Mg(2+) loss. Our results are in line with the hypothesis that EGF influences the renal expression or activation of TRPM6 and plays a significant role in Mg(2+) loss in medication-induced nephropathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption / drug effects
  • Animals
  • Cisplatin / adverse effects*
  • Claudins / genetics
  • Claudins / metabolism
  • Down-Regulation / drug effects*
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / metabolism
  • Kidney / cytology
  • Kidney / drug effects*
  • Kidney / metabolism*
  • Magnesium / metabolism
  • Male
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*

Substances

  • Claudins
  • TRPM Cation Channels
  • TRPM6 protein, rat
  • claudin 16
  • Epidermal Growth Factor
  • ErbB Receptors
  • Trpm7 protein, rat
  • Magnesium
  • Cisplatin

Grant support

This study was supported by a research grant for KJL from the University of Antwerp. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.