吡格列酮对载脂蛋白E~(-/-)小鼠脂质肾损伤的干预研究
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摘要
目的:探讨吡格列酮(piog litazone, Piog)对老年雌性载脂蛋白E基因敲除(apoE~(-/-))小鼠脂质肾损伤的干预作用及可能机制。方法:13个月龄雌性apoE~(-/-)小鼠随机分为2组,实验组灌胃盐酸吡格列酮(每只10 mg·kg~(-1)·d~(-1)),对照组灌胃同体积溶媒0.5%羧甲基纤维素钠。12周后对小鼠实施安乐死进行取材。灌胃前后进行血浆总胆固醇(TC)、三酰甘油(TG)及髓过氧化物酶(MPO)活性测定,肾脏石蜡切片进行组织化学染色分析肾脏损伤程度及脂质沉积情况,实时定量PCR(QPCR)分析相关基因mRNA表达水平。结果:与对照组比较,Piog组小鼠血浆TC、TG水平及MPO活性明显降低;Masson染色示肾脏纤维化程度明显降低;网状纤维染色示肾皮质中Ⅳ型胶原蛋白(ColⅣ)为主的网状纤维增生程度减轻;PAS染色示肾小球硬化、基底膜增生增厚情况得到改善;油红O染色示肾脏脂质沉积情况减轻。QPCR结果示肾皮质过氧化物酶体增殖物激活受体-γ(PPARγ)及对氧磷酶-1(PON1)mRNA水平升高,而肿瘤坏死因子-α(TNF-α)、单核细胞趋化因子-1(MCP-1)、转化生长因子-β(TGF-β)、CollagenⅣ和基质金属蛋白酶(MMP-2、MMP-9)的mRNA水平降低。结论:吡格列酮能够改善老年apoE~(-/-)小鼠脂质紊乱引发的肾脏病理性损伤,其机制可能与PPARγ激活而调脂及降低小鼠全身和肾脏局部氧化炎症状态有关。
OBJECTIVE To investigate the effect and possible mechanism of pioglitazone(Piog) on lipid induced renal injury in aged female apolipoprotein E knockout(apoE~(-/-)) mice. METHODS Sixteen thirteen-month-old female apoE~(-/-) mice were randomly divided into two groups. The experimental group was intragastrically administered with pioglitazone hydrochloride(10 mg·kg~(-1)·d~(-1)), and the control group was intragastrically administered 0.5% sodium carboxymethylcellulose in the same volume of vehicle.for 12 weeks, then the mice were euthanized. The levels of plasma total cholesterol(TC), triglyceride(TG) and the activity of myeloperoxidase(MPO) were measured before and after perfusion. Renal paraffin embedded sections were used for histochemical staining to analyze the degree of renal injury and lipid deposition. mRNA expression levels of related genes were analyzed by quantitative RT-PCR(QPCR) method.RESULTS Compared with control group, plasma TC, TG levels and MPO activity in Piog group were significantly decreased; Masson staining showed that the degree of renal fibrosis was significantly lower; reticular fiber staining showed that the degree of collagen Ⅳ(Col Ⅳ)-based reticular fiber proliferation in the renal cortex was reduced; PAS staining revealed that the glomerular sclerosis and basement membrane proliferation and thickening were improved; Oil red O staining showed that the renal lipid deposition was significantly reduced. Furthermore, QPCR results showed the renal mRNA level of peroxisome proliferator-activated receptor γ(PPARγ) and paraoxonase-1(PON1) was increased, while tumor necrosis factor-α(TNF-α)、monocyte chemotactic factor-1(MCP-1), collagen Ⅳ, matrix metalloproteinases(MMP-2, MMP-9) were decreased. CONCLUSION Piog can ameliorate the renal pathological injury induced by lipid disorder in aged apoE~(-/-) mice, and the mechanism may be related to the activation of PPARγ-to regulate lipid and decrease the systemic and local oxidative inflammation in mice.
OBJECTIVE To investigate the effect and possible mechanism of pioglitazone(Piog) on lipid induced renal injury in aged female apolipoprotein E knockout(apoE~(-/-)) mice. METHODS Sixteen thirteen-month-old female apoE~(-/-) mice were randomly divided into two groups. The experimental group was intragastrically administered with pioglitazone hydrochloride(10 mg·kg~(-1)·d~(-1)), and the control group was intragastrically administered 0.5% sodium carboxymethylcellulose in the same volume of vehicle.for 12 weeks, then the mice were euthanized. The levels of plasma total cholesterol(TC), triglyceride(TG) and the activity of myeloperoxidase(MPO) were measured before and after perfusion. Renal paraffin embedded sections were used for histochemical staining to analyze the degree of renal injury and lipid deposition. mRNA expression levels of related genes were analyzed by quantitative RT-PCR(QPCR) method.RESULTS Compared with control group, plasma TC, TG levels and MPO activity in Piog group were significantly decreased; Masson staining showed that the degree of renal fibrosis was significantly lower; reticular fiber staining showed that the degree of collagen Ⅳ(Col Ⅳ)-based reticular fiber proliferation in the renal cortex was reduced; PAS staining revealed that the glomerular sclerosis and basement membrane proliferation and thickening were improved; Oil red O staining showed that the renal lipid deposition was significantly reduced. Furthermore, QPCR results showed the renal mRNA level of peroxisome proliferator-activated receptor γ(PPARγ) and paraoxonase-1(PON1) was increased, while tumor necrosis factor-α(TNF-α)、monocyte chemotactic factor-1(MCP-1), collagen Ⅳ, matrix metalloproteinases(MMP-2, MMP-9) were decreased. CONCLUSION Piog can ameliorate the renal pathological injury induced by lipid disorder in aged apoE~(-/-) mice, and the mechanism may be related to the activation of PPARγ-to regulate lipid and decrease the systemic and local oxidative inflammation in mice.
引文
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[15] Gungor O,Kircelli F,Toz H.Paraoxonase 1,atherosclerosis and arterial stiffness in renal patients[J].Int Urol Nephrol,2013,45(2):441-447.
[16] Yu YB,Chen X,Cheng L,et al.Effects of pioglitazone on Toll-like receptor 4/mitogen-activated protein kinase pathway in atherosclerosis of apolipoprotein E knockout mice[J].Chin J Cardiovasc Med (中国心血管杂志),2014,19(6):444-448.
[2] Ratliff BB,Abdulmahdi W,Pawar R,et al.Oxidant mechanisms in renal injury and disease[J].Antioxid Redox Signal,2016,25(3):119-146.
[3] Bonomini F,Rodella LF,Moghadasian M,et al.Role of apolipoprotein E in renal damage protection[J].Histochem Cell Biol,2011,135(6):571-579.
[4] Derosa G,Maffioli P.Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists on glycemic control,lipid profile and cardiovascular risk[J].Curr Mol Pharmacol,2012,2:272-281.
[5] Hong F,Xu P,Zhai Y.The opportunities and challenges of peroxisome proliferator-activated receptors ligands in clinical drug discovery and development[J].Int J Mol Sci,2018,19(8)2189.
[6] Zhou HY,Hu JP,Yan ZD,et al.Effects of pioglitazone on ectopic lipid accumulation in skeletal muscles in rats fed with high fat diet[J].Chin Hosp Pharm J (中国医院药学杂志),2015,35(3):233-236.
[7] Wang AF,Xia T,Zhang QP,et al.Effects of pioglitazone on the expression of TNF-αin kidney of obese mice[J].J Tianjin Med Univ (天津医科大学学报),2015,21(3):229-232.
[8] Pourshabanan P,Momeni A,Mahmoudnia L,et al.Effect of pioglitazone on decreasing of proteinuria in type 2 diabetic patients with nephropathy[J].Diabetes Metab Syndr,2019,13(1):132-136.
[9] Shen D,Li H,Zhou R,et al.Pioglitazone attenuates aging-related disorders in aged apolipoprotein E deficient mice[J].Exp Gerontol,2018,102:101-108.
[10] Chagnac A,Weinstein T,Korzets A,et al.Glomerular hemodynamics in severe obesity[J].Am J Physiol Renal Physiol,2000,278(5):F817-F822.
[11] Dong B,Chen W,Cheng H,et al.Clinicopathological features of obesity-associated focal segmental glomerulosclerosis[J].Chin J Nephrol (中华肾脏病杂志),2002,18(6):389-392.
[12] Lv W,Booz GW,Fan F,et al.Oxidative stress and renal fibrosis:recent insights for the development of novel therapeutic strategies[J].Front Physiol,2018,9:105.
[13] Corrales P,Izquierdo-Lahuerta A,Medina-Gómez G.Maintenance of kidney metabolic homeostasis by PPAR gamma[J].Int J Mol Sci,2018,19(7),2063.
[14] Urakami-Takebayashi Y,Kuroda Y,Murata T,et al.Pioglitazone induces hypoxia-inducible factor 1 activation in human renal proximal tubular epithelial cell line HK-2[J].Biochem Biophys Res Commun,2018,503(3):1682-1688.
[15] Gungor O,Kircelli F,Toz H.Paraoxonase 1,atherosclerosis and arterial stiffness in renal patients[J].Int Urol Nephrol,2013,45(2):441-447.
[16] Yu YB,Chen X,Cheng L,et al.Effects of pioglitazone on Toll-like receptor 4/mitogen-activated protein kinase pathway in atherosclerosis of apolipoprotein E knockout mice[J].Chin J Cardiovasc Med (中国心血管杂志),2014,19(6):444-448.