Epidermal growth factor receptor inhibition with erlotinib partially prevents cisplatin-induced nephrotoxicity in rats.
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.
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Yukihiro
Y
Wada
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Masayuki
M
Iyoda
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Kei
K
Matsumoto
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Yuki
Y
Shindo-Hirai
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Yoshihiro
Y
Kuno
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Yasutaka
Y
Yamamoto
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Taihei
T
Suzuki
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Tomohiro
T
Saito
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Ken
K
Iseri
Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Takanori
T
Shibata
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D017209:Apoptosis; D001835:Body Weight; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D002945:Cisplatin / Q000009:adverse effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D008099:Liver / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D002945:Cisplatin