Abstract: Objective To investigate the molecular mechanisms of vascular smooth muscle cell (VSMC) hyperplasia and extracellular signal-regulated protein kinase 1/2 (ERK 1/2) phosphorylation of VSMCs under the condition of hypertension. Methods Wistar rat models of two kidney-one clip hypertension (2K1C) were established and their right kidneys were harvested 4 weeks after the operation. Immunohistochemistry and Western blotting were performed to detect phospho-ERK1/2 and P21ras protein expression in the VSMCs of the renal arterioles, and the results were compared with those from 16-week-old spontaneous hypertension rats (SHR16) and control rats. Results The blood pressure of 2K1C Wistar rats was significantly increased from 104±18 mmHg to 198±33 mmHg at the end of the experiment, and the blood pressure of SHR16 reached 163±23 mmHg, significantly higher than that of the control rats (P<0.01). Compared with the control group, 2K1C rats showed obvious glomerular fibrosis (P<0.05) with hyaline degeneration of the afferent arterioles. In contrast, neither glomerular fibrosis nor hyaline degeneration of arterioles, nor protein cast was observed in SHR16. In 2K1C rats and SHR16, the positivity rates of phospho-ERK1/2 and p21ras staining in the VSMCs of the afferent arterioles and the interlobular, interlobar and arcuate arteries was significantly higher than those of the controls (P<0.01), and the expression of phospho-ERK1/2 and P21ras protein in the kidney was also significantly higher as revealed by Western blotting (P<0.01). Conclusion High expression of ERK1/2 and P21ras in the renal arteriole VSMCs of 2K1C hypertensive rats and SHR may play an important role in VSMC hypertrophy and proliferation in hypertension.