Naringenin Ameliorates Hypertensive Renal Damage And Normalizes The Balance Of Renin-Angiotensin System Components In Rats

Background.Naringenin,a member of the dihydroflavone family,with biological activities of antiinflammation and antioxidation,has been shown to have a protective function in multiple diseases,including cardiovascular diseases,diabetes mellitus,central nervous system diseases and cancers.We previously demonstrated that naringenin inhibited hypertensive myocardial hypertrophy in rats by decreasing local angiotensin-converting enzyme(ACE)expression.Objective.The kidney is a primary target organ of hypertension,the present study aimed to test the effect of naringenin on renovascular hypertensive kidney damage and to explore the underlying mechanism.Methods.An animal model of renovascular hypertension was established by performing two-kidney,one-clip(2K1C)surgery in Sprague Dawley rats.Naringenin(200 mg/kg.bw/day)or vehicle saline(equal volume)was administered intragastrically to rats for 10 weeks.Sham operation was performed and vehicle saline was given to control rats.Blood pressure and urinary protein were continuously monitored.Renal pathology,plasma angiotensin ?(Ang ?)and angiotensin 1-7(Ang 1-7)levels,and local gene expression of renin-angiotensin system of nonclipped kidneys were evaluated separately by histology,enzyme-linked immunosorbent assay,real-time polymerase chain reaction,immunohistochemistry and Western blot at the end of the study.Results.Compared with controls,rats that underwent 2K1C surgery plus saline exhibited marked elevations of blood pressure(163.2±15.3 mmHg vs.108.2±1.7 mmHg,p=0.0015),as well as albuminuria and renal damage(20.51± 10.63mg vs.1.356±0.4023 mg,p<0.001),including mesangial expansion,interstitial fibrosis,and arteriolar thickening in the nonclipped kidneys.Naringenin significantly ameliorated hypertensive nephropathy(p<0.001),without retarding the rise of urine protein(12.85±10.38mg vs.20.51±10.63mg,p=0.62),and had no effect on blood pressure(182.6±19.59mmHg vs.163.2±15.3 mmHg,p=0.27).Plasma Ang II levels were significantly higher in 2K1C rats than in sham rats(13.27±1.78 pg/ml vs.7.20±0.48 pg/ml,p=0.011).In the nonclipped kidneys,the expression of mRNA of AT2R(angiotensin ? type 2 receptor)was downregulated ACE protein expression was increased,ACE2(angiotensin-converting enzyme 2)protein expression and the ACE/ACE2 protein ratio was decreased,protein expression of AT2R in the renal medulla was decreased and AT1R/AT2R protein ratio was in both the cortex and medulla Compared with the control group,2K1C group had less of nonclipped kidneys,and naringenin prevented the decrease.of nonclipped kidneys in model animals,and the increasing ratios were inhibited in 2K1C plus naringenin group.All these changes were significantly suppressed by naringenin administration.Conclusions.In the present study,naringenin attenuated hypertensive renal damage as well as prevented the imbalanced activation of systemic and local renin-angiotensin system in renovascular hypertensive rats.Our results suggest that naringenin-related drugs may be a potential treatment strategy for hypertensive nephropathy.