Effect of erlotinib on renal injury in rats with STZ-induced diabetic nephropathy

Tian HUANG; Xi CAI; Ling ZHONG

ABSTRACT

AIM:

To investigate the effect of epidermal growth factor receptor (EGFR) inhibitor erlotinib on kidney injury in diabetic nephropathy (DN) rat and the underlying mechanism.

METHODS:

The rat model of DN was induced by intraperitoneal injection of streptozotocin (STZ) at dose of 55 mg/kg.One week after STZ injection, the rats with blood glucose level exceeding 16.7 mmol/L were identified as diabetic.Diabetic rats were randomly divided into 2 groups STZ group and STZ+erlotinib group.In addition, the normal rats were used as control group.The rats in STZ+erlotinib group were treated with erlotinib at 100 mg·kg-1·d-1 for 4 weeks(5th~8th week).The fasting blood glucose (FBG), serum creatinine (SCr) and 24 h urine protein were measured.The pathological changes of the kidney were observed by HE staining and Masson staining.The protein levels of EGFR, p-EGFR, transforming growth factor β1 (TGFβ1), Smad2/3, p-Smad2/3, collagen Ⅳ (ColⅣ) and fibronectin in the kidney tissues were determined by Western blot.The reactive oxygen species (ROS) level and malondialdehyde (MDA) content in the renal tissues were futher analyzed.

RESULTS:

Compared with control group, the levels of FBG, 24 h urine protein and Scr were significantly increased in STZ group (P<0.01).Compared with STZ group, the levels of FBG, 24 h urine protein and SCr in STZ+erlotinib group were markedly decreased (P<0.05).In additon, the glomerular structure was restored to normal, the proliferative degree of mesangial cells markedly attenuated, and the epithelial cells were in alignment in STZ+erlotinib group.Moreover, erlotinib significantly inhibited the protein levels of p-EGFR, TGFβ1, p-Smad2/3, ColⅣ and fibronectin in the kidney tissues of STZ rats.In addition, erlotinib also significantly inhibited the levels of ROS and MDA in the kidney tissues of STZ rats.

CONCLUSION:

Erlotinib ameliorates STZ-induced diabetic nephropathy possibly through inhibiting the activation of EGFR/TGFβ1-Smad2/3 signaling pathway in association with suppression of fibrosis and oxidative stress.