Epidermal Growth Factor Receptor Inhibition With Erlotinib Partially Prevents Cisplatin-Induced Nephrotoxicity in Rats

PLoS One. 2014 Nov 12;9(11):e111728. doi: 10.1371/journal.pone.0111728. eCollection 2014.

Abstract

The effects of blocking the epidermal growth factor receptor (EGFR) in acute kidney injury (AKI) are controversial. Here we investigated the renoprotective effect of erlotinib, a selective tyrosine kinase inhibitor that can block EGFR activity, on cisplatin (CP)-induced AKI. Groups of animals were given either erlotinib or vehicle from one day before up to Day 3 following induction of CP-nephrotoxicity (CP-N). In addition, we analyzed the effects of erlotinib on signaling pathways involved in CP-N by using human renal proximal tubular cells (HK-2). Compared to controls, rats treated with erlotinib exhibited significant improvement of renal function and attenuation of tubulointerstitial injury, and reduced the number of apoptotic and proliferating cells. Erlotinib-treated rats had a significant reduction of renal cortical mRNA for profibrogenic genes. The Bax/Bcl-2 mRNA and protein ratios were significantly reduced by erlotinib treatment. In vitro, we observed that erlotinib significantly reduced the phosphorylation of MEK1 and Akt, processes that were induced by CP in HK-2. Taken together, these data indicate that erlotinib has renoprotective properties that are likely mediated through decreases in the apoptosis and proliferation of tubular cells, effects that reflect inhibition of downstream signaling pathways of EGFR. These results suggest that erlotinib may be useful for preventing AKI in patients receiving CP chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects
  • Apoptosis
  • Body Weight
  • Cell Line
  • Chemical and Drug Induced Liver Injury / drug therapy*
  • Cisplatin / adverse effects*
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride
  • Humans
  • Kidney Tubules, Proximal / drug effects
  • Liver / drug effects*
  • Macrophages / drug effects
  • Male
  • Phosphorylation
  • Protein Kinase Inhibitors / therapeutic use*
  • Quinazolines / therapeutic use*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Quinazolines
  • RNA, Messenger
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Cisplatin

Grant support

YW and YK were supported by a Showa University Research Grant for Young Researchers. MI was supported by the Showa University Medical Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.