目的 探讨缬沙坦对糖尿病肾损害大鼠肾脏足细胞凋亡及内质网应激标志性蛋白GRP78、caspase12表达的影响。方法 将雄性SD大鼠随机分为正常对照组和实验组。实验组大鼠给予腹腔注射链脲佐菌素建立糖尿病模型,然后随机将其分为模型组和缬沙坦组,正常对照组和模型组1次/d给予反渗水灌胃,缬沙坦组1次/d给予缬沙坦(8 mg/kg)灌胃,时间为6周。对nephrin、GRP78、caspase12表达水平进行分析,同时观察血糖、血尿素氮、肌酐、24 h尿蛋白定量等指标。结果 建模第6周,模型组大鼠肾脏较正常对照组凋亡细胞数明显增多,模型组GRP78(6.75±0.65)及caspase12(11.51±0.32)表达较正常对照组GRP78(1.57±0.39)、caspase12(2.66±0.57)增强(P＜0.05),模型组nephrin(2.29±0.15)较正常对照组(5.71±0.53)表达减少(P＜0.05)。缬沙坦组较模型组凋亡细胞数减少,GRP78(3.14±1.00)、caspase12(8.08±2.48)表达减弱(P＜0.05),nephrin(3.35±0.40)表达减少较轻(P＜0.05)。结论 缬沙坦通过减缓内质网应激并可能通过抑制内质网特有的caspase12凋亡途径,减少足细胞的凋亡,从而发挥对糖尿病肾病的保护作用。
Abstract
Objective To evaluate the effect of valsartan on apoptosis of podocytes,GRP78 which serve as a symbolic protein of endoplasmic reticulum stress (ERS) and caspase12 in diabetic rats. Methods Male SD rats were randomly divided into normal group and study group.The animal models with diabetes were established in study group by STZ intraperitoneal injection,then the study group were randomly divided into model group and valsartan group.Water was aiministered daily by gavage to normal group and model group.Valsartan was administered daily by gavage to valsartan group for 6 weeks. The levels of protein of nephrin、GRP78,caspase 12.BG,Cr ,BUN and 24-hour urinary protein quantity were checked. Results At the time of 6 weeks,compared with those in normal group,the number of apoptosis cells were much higher in the model kidneys,the expression of GRP78(6.75±0.65),caspase 12 (11.51±0.32)in the model kidneys were much higher than GRP78(1.57±0.39),caspase12(2.66±0.57)in the normal group(P＜0.05);however, the expression of nephrin in the model group(2.29±0.15)was lower than in the normal group(5.71±0.53)(P＜0.05). While in the valsartan group,reductions were found in the expression of GRP78(3.14±1.00),caspase12 (8.08±2.48)and the number of apoptotic cells(P＜0.05),the expression of nephrin (3.35±0.40)was higher(P＜0.05). Conclusions Valsartan can depress the effect of endoplasmic reticulum stress and reduce the apotosis of the podocytes in the development of diabetic nephropathy.
关键词
糖尿病肾病 /
内质网应激 /
足细胞凋亡 /
nephrin蛋白 /
缬沙坦
Key words
diabetic nephropathy /
endoplasmic reticulum stress /
apoptosis /
nephrin /
valsartan
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] Toycda M, Suzuki D. Expression of human nephrin mRNA in diabetic nephropathy[J]. Nephrol Dial Transplant,2004,19(3):380-385.
[2] Butt A, Riaz S.Study of protein profiling of human urine in diabetic hypertensive nephropathy versus normal healthy controls[J].Diabetes Technol Ther, 2010,12(5):379-386.
[3] Chen M, Felix K, Wang J.Immune regulation through mitochondrion-dependent dendritic cell death induced by T regulatory cells [J].J Immunol,2011,187(11):5684-5692.
[4] Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response[J].Nat Rev Mol Cell Biol,2007, 8(7):519-529.
[5] Kriz W. Progressive renal failure-inability of podocytes to replicate and the consequences for development of glomerulosckerosis[J].Nephrol Dial Transplant,1996,11(9):1738-1742.
[6] Liu G, Sun Y, Li Z,et al. Apoptosis induced by endoplasmic reticulum stress involved in diabetic kidney disease [J].Biochem Biophys Res Commun,2008,13,370(4):651-656.
[7] Schroder M, Kaufman R J.The mammalian unfolded protein response[J]. Annu Rev Biochem,2005,74:739-789.
[8] Ni M, Lee A S.Echaperones in mammalian development and human diseases[J].FEBS Lett,2007,581(19):3641-3651.
[9] Ohse T, Inagi R, Tanaka T,et al. Albumin induces endoplasmic reticulum stress and apoptosis in renal proximal tubular cells[J].Kidney Int,2006,70(8):1447-1455.
[10] Davis B J, Cao Z, Gaparo M,et al.Disparate effects of angiotensin Ⅱ antagonists and calcium channel blockers on albuminuria in experimental diabetes and hypertension:potential role of nephrin[J]. Hypertens,2003,21(1):209-216.
[11] Davis B J, Forbes J M, Thomas M C, et al.Superior renoprotective effects of combination therapy with ACE and AGE inhibition in the diabetic spontaneously hypertensive rat[J].Diabetologia,2004,47(1):89-97.
[12] 陈玉凤,张会娟,沈育芬,等.替米沙坦对糖尿病大鼠肾脏组织中内质网应激介导相关细胞凋亡的保护作用[J].中华内分泌代谢杂志,2011,27(9):849-852.
基金
国家自然科学基金面上项目(81273706)
PDF(1499 KB)
