Abstract: Objective To investigate the alteration of renal podocyte Nephrin signaling and ultrastructural injury in hypertension state and the effects of recombinant human angiotensin-converting enzyme 2（rhACE2）on these alterations. Methods The 10-or 11-week C57/B6 mice were randomized to three groups,including the normal control group（n=8）,the hypertension+placebo group（n=6）and the hypertension+rhACE2treatment group（n=6）.Hypertensive model was established by infusion of angiotensin Ⅱ（Ang Ⅱ）daily with the dose of 1.5mg/kg,and the hypertensive mice were then treated with rhACE2（2mg/kg per day,intraperitoneal）or placebo for 2weeks.The systolic blood pressure（SBP）of mice was measured by the tail-cuff method. Nephrin protein and malonyldialdehyde（MDA）concentrations in mouse kidneys were determined with Western blot and thiobarbituric acid（TBA）reactive substances methods,respectively. In addition,renal ultrastructure was observed via transmission electron microscope. Results Compared with control group,SBP levels were obviously elevated in the Ang Ⅱ-induced hypertensive mice（156.2±9.8）vs（100.8±9.9）mm Hg,P＜0.01,associated with reduced Nephrin protein levels and enhanced MDA contentNephrin:0.48±0.06 vs 1.00±0.08 and MDA（159.6±12.1）vs（55.2±9.0）nmol/g,P＜0.01,respectively. Compared with hypertension+placebo group,treatment with rhACE2 significantly decreased SBP levels（134.8±8.3）vs（156.2±9.8）mm Hg,P＜0.05,and promoted renal Nephrin levels in hypertensive mice,along with a marked reduction in MDA contentsNephrin:0.71±0.07 vs 0.48±0.06 and MDA（98.5±11.5）vs（159.6±12.1）nmol/g,P＜0.05,respectively. Finally,treatment with rhACE2 strikingly attenuated renal ultrastructure injury in hypertensive mice,characterized with the decrease of vacuolizated mitochondria in renal tubular,and improvement of the thickening glomerular capillary basement membrane and foot process effacement in podocytes. Conclusions There are diminished Nephrin signaling,augmented oxidative stress and ultrastructure injury in kidneys of hypertensive mice. Treatment with rhACE2 can improve renal expression of Nephrin,which further contribute to attenuation of oxidative stress and renal ultrastructure injury in hypertensive mice,implying that ACE2 has a potential renoprotective effect in hypertension.