过氧化酶体增殖体受体激动剂延缓大鼠肾脏衰老的实验研究
|
摘要
肾脏衰老一直是临床与基础研究都非常感兴趣的问题,随着衰老,肾脏的形态以及功能都发生显著的改变,肾小球滤过率不依赖于明显的病理改变而逐渐下降,衰老导致了肾小球、血管、肾脏实质等一系列改变。诸如高血压、糖尿病都可以对老龄肾脏造成一定的损伤。我们的研究以肾脏衰老为突破口,以此发现器官衰老的主要环节,揭示器官衰老的一些共同机制,提出延缓衰老的有效措施。本课题拟在原有的研究基础上,从肾脏衰老入手,观察PPARγ在。肾脏表达的随龄变化情况,证实PPARγ在肾脏衰老中的作用。动物实验验证PPARγ激动剂罗格列酮治疗肾脏衰老的安全性和有效性,从氧化应激状态、信号传导调节细胞周期影响细胞分化等角度对其抗衰老的分子机制进行初步探讨,并运用代谢组学的技术开展延缓大鼠肾脏衰老的分析和生物标记物发现,将分子生物学与代谢组学技术结合起来,探索抗肾脏衰老的新方法、新途径。
我们以3月、12月、24月自然衰老SD大鼠为模型,分别代表青年组、中年组、老年组。免疫组化显示PPARγ在各年龄组大鼠肾组织的肾小管、集合管上皮细胞中均有分布,主要分布于细胞核内,胞浆内也有少量表达,在老年大鼠皮质肾小球系膜区系膜细胞、偶尔在壁层上皮细胞内也有阳性染色。原位杂交结果进一步在mRNA水平上证实了这一结果。免疫印迹分析结果显示PPARγ蛋白在大鼠肾脏衰老过程中表达下降。SOD、GStt-Px两种衰老标志物在大鼠肾脏衰老过程中含量也出现下降,并且两组数据呈正相关。在第二部分研究里,以罗格列酮干预中年、老年大鼠12周,以能量限制为阳性对照组。发现PPARγ蛋白在中年、老年罗格列酮及限食组的大鼠肾脏中的表达均上调。作为衰老标志物的P16在中年、老年罗格列酮组及限食组均出现不同程度的降低。P53蛋白在老年及中年各组大鼠中表达差异均不明显。推测罗格列酮在增强动物抗氧化能力的同时,可能通过调节P16/Rb信号转导通路,下调P16的表达减轻对pRb的抑制,细胞周期阻滞缓解得以顺利进行,从而增强了中年、老年大鼠肾脏细胞的增生分化能力。另外在实验中还发现罗格列酮能降低中年及老年大鼠的血清胆固醇、甘油三酯水平,加强其分解对衰老肾脏起到保护作用。在第三部分实验中我们收集了老年对照组、罗格列酮组、能量限制组大鼠的血液样品,运用液质联用的代谢组学方法(HPLC/Ms),通过比较进入动物血清化学成分及代谢物谱,考察了罗格列酮延缓大鼠肾脏衰老的物质基础。发现各组图中主成分积分值基本集中分布于椭圆形散点图的几个区域,各组间无明显交叉和重叠。正常组与罗格列酮组、能量限制组之间有着代谢产物的不同,说明血浆代谢组学分析能够较好地反映罗格列酮干预组与正常对照组及能量限制组之间的差异。在图谱中可以发现肉毒碱(Carnitine)、植物鞘氨醇(Phytosphingosine)、棕榈酰磷脂胆碱(Palmitoyllysophosphatidylcholine)、甘油磷酰胆碱(stearoylglycerophosphocholine)等脂质化合物改变较为明显,这些发生改变的代谢物可以作为罗格列酮延缓老年大鼠肾脏衰老的生物标志物做进一步的研究。并且上述脂质化合物与能量代谢、脂肪代谢途径密切相关,这些代谢物的改变提示罗格列酮干预后动物能量代谢及脂肪代谢功能均发生了变化,这可能是老年大鼠肾脏衰老发生、发展的潜在原因,从而揭示了罗格列酮延缓肾脏衰老的生物学本质。
综上所述我们认为PPARγ参与了大鼠肾脏衰老的调控,PPARγ激动剂罗格列酮可以增强老年动物抗氧化应激能力,通过抑制肿瘤抑制因子P16的表达而调节细胞周期、增强衰老肾脏细胞的增生分化能力,并能调节老年大鼠自身脂肪代谢紊乱,增加甘油三酯的分解,增强胰岛素敏感性,从而保护肾组织延缓了衰老。
Aging of the kidney is a problem of clinical and basic interest.The glomerular filtration rate falls progressively,independent of overt pathology.Glomerular,vascular and accompanying parenchymal changes occur and other disorders associated with ageing,such as diabetes and hypertension,have a stochastic deleterious effect on both form and function.We focus our research on kidney aging to reveals the common mechanism and provide the effective measures.Present study will be based on the original research to observe the expression and the role of the PPARγduring the rat kidney aging.In the research,we attempt to document the safety and effectiveness of PPARγagonist rosiglitazone by animal experiment,and futher to explore the molecular regulation of PPARγduring the aging process.The beneficial effects of PPARγagonist antiaging can be analysized through the cellular signal transduction activities and the modulation of various redox-sensitive transcription factors.In addition,the effect of Rosiglitazone delaying kidney ageing in rat will be demonstrated by metabonomic technique and to dicover the biomarker of it.We will combine the molecular biology and metabonomics to provide a new method and pathway of preventing rat kidney aging.
We made the 3month,12month and 24month natural aging rat as model which represent young,middle-aged and old group respectively.Significant expression of PPARγprotein were detected in the cell of renal tubule and collecting duct in each group by immunohistochemistry.PPARγprotein expression was observed as nuclear and cytoplasmic staining.In old age group PPARγprotein were also observed little in the mesangial cells and Bowman capsul's epithelial cell.However,hybridization in situ also verified the above result at mRNA level.Westernblot result shows that PPARγprotein decreased with age,while the activity of superoxide dismutase(SOD) and Glutathione peroxidase(GSH-PX) in rat kidney were decreased.The activity of SOD and GSH-PX were positively correlated with the expressions of PPARγ.In the second part,we designated the calorie restriction group as positive control while treated the middle-aged rat group and old rat group with RGTZ.We find the expression of PPARγprotein increased in RGTZ and CR groups in middle-aged and old rat kidney tissue compared with control group.P53 protein were no obvious different among different groups. Collecting the serum samples of each old rat group,we confirmed the chemical componds and final products of metabolism in the rat serm by HPLC/MS analysis.The results declare that the principle component score was usually distributed in several regions of the scatterplot ellipse graph,and each group has no obvious acrossing.The metabolism products are significantly different among every group.In this study,5 biomarkers were structurally proposed and all these metabolites will provide more information to study the mechanism of preventing rat kidney senescence.In addition,the lipid componds are closely connected with energy and lipid metabolism.It is conceivable that all of the differences observed here investigate that the energy and lipid metabolism in animal have changed much,and perhaps it is the potential reason to induce aging.
All above were summarized as following:PPARγparticipate in the regulating of rat kidney aging.Date further revealed that PPARγagonist enhance the old animal's ability to anti-oxidative stress,reduce the expression of tumor inhibit factor P16. Preventing kidney aging of RGTZ,also provide a better understanding of the role of PPARγ,which can regulate the disorder of lipid metabolism,increase the breakdown of TG,and enhance the sensibility of insulin.
我们以3月、12月、24月自然衰老SD大鼠为模型,分别代表青年组、中年组、老年组。免疫组化显示PPARγ在各年龄组大鼠肾组织的肾小管、集合管上皮细胞中均有分布,主要分布于细胞核内,胞浆内也有少量表达,在老年大鼠皮质肾小球系膜区系膜细胞、偶尔在壁层上皮细胞内也有阳性染色。原位杂交结果进一步在mRNA水平上证实了这一结果。免疫印迹分析结果显示PPARγ蛋白在大鼠肾脏衰老过程中表达下降。SOD、GStt-Px两种衰老标志物在大鼠肾脏衰老过程中含量也出现下降,并且两组数据呈正相关。在第二部分研究里,以罗格列酮干预中年、老年大鼠12周,以能量限制为阳性对照组。发现PPARγ蛋白在中年、老年罗格列酮及限食组的大鼠肾脏中的表达均上调。作为衰老标志物的P16在中年、老年罗格列酮组及限食组均出现不同程度的降低。P53蛋白在老年及中年各组大鼠中表达差异均不明显。推测罗格列酮在增强动物抗氧化能力的同时,可能通过调节P16/Rb信号转导通路,下调P16的表达减轻对pRb的抑制,细胞周期阻滞缓解得以顺利进行,从而增强了中年、老年大鼠肾脏细胞的增生分化能力。另外在实验中还发现罗格列酮能降低中年及老年大鼠的血清胆固醇、甘油三酯水平,加强其分解对衰老肾脏起到保护作用。在第三部分实验中我们收集了老年对照组、罗格列酮组、能量限制组大鼠的血液样品,运用液质联用的代谢组学方法(HPLC/Ms),通过比较进入动物血清化学成分及代谢物谱,考察了罗格列酮延缓大鼠肾脏衰老的物质基础。发现各组图中主成分积分值基本集中分布于椭圆形散点图的几个区域,各组间无明显交叉和重叠。正常组与罗格列酮组、能量限制组之间有着代谢产物的不同,说明血浆代谢组学分析能够较好地反映罗格列酮干预组与正常对照组及能量限制组之间的差异。在图谱中可以发现肉毒碱(Carnitine)、植物鞘氨醇(Phytosphingosine)、棕榈酰磷脂胆碱(Palmitoyllysophosphatidylcholine)、甘油磷酰胆碱(stearoylglycerophosphocholine)等脂质化合物改变较为明显,这些发生改变的代谢物可以作为罗格列酮延缓老年大鼠肾脏衰老的生物标志物做进一步的研究。并且上述脂质化合物与能量代谢、脂肪代谢途径密切相关,这些代谢物的改变提示罗格列酮干预后动物能量代谢及脂肪代谢功能均发生了变化,这可能是老年大鼠肾脏衰老发生、发展的潜在原因,从而揭示了罗格列酮延缓肾脏衰老的生物学本质。
综上所述我们认为PPARγ参与了大鼠肾脏衰老的调控,PPARγ激动剂罗格列酮可以增强老年动物抗氧化应激能力,通过抑制肿瘤抑制因子P16的表达而调节细胞周期、增强衰老肾脏细胞的增生分化能力,并能调节老年大鼠自身脂肪代谢紊乱,增加甘油三酯的分解,增强胰岛素敏感性,从而保护肾组织延缓了衰老。
Aging of the kidney is a problem of clinical and basic interest.The glomerular filtration rate falls progressively,independent of overt pathology.Glomerular,vascular and accompanying parenchymal changes occur and other disorders associated with ageing,such as diabetes and hypertension,have a stochastic deleterious effect on both form and function.We focus our research on kidney aging to reveals the common mechanism and provide the effective measures.Present study will be based on the original research to observe the expression and the role of the PPARγduring the rat kidney aging.In the research,we attempt to document the safety and effectiveness of PPARγagonist rosiglitazone by animal experiment,and futher to explore the molecular regulation of PPARγduring the aging process.The beneficial effects of PPARγagonist antiaging can be analysized through the cellular signal transduction activities and the modulation of various redox-sensitive transcription factors.In addition,the effect of Rosiglitazone delaying kidney ageing in rat will be demonstrated by metabonomic technique and to dicover the biomarker of it.We will combine the molecular biology and metabonomics to provide a new method and pathway of preventing rat kidney aging.
We made the 3month,12month and 24month natural aging rat as model which represent young,middle-aged and old group respectively.Significant expression of PPARγprotein were detected in the cell of renal tubule and collecting duct in each group by immunohistochemistry.PPARγprotein expression was observed as nuclear and cytoplasmic staining.In old age group PPARγprotein were also observed little in the mesangial cells and Bowman capsul's epithelial cell.However,hybridization in situ also verified the above result at mRNA level.Westernblot result shows that PPARγprotein decreased with age,while the activity of superoxide dismutase(SOD) and Glutathione peroxidase(GSH-PX) in rat kidney were decreased.The activity of SOD and GSH-PX were positively correlated with the expressions of PPARγ.In the second part,we designated the calorie restriction group as positive control while treated the middle-aged rat group and old rat group with RGTZ.We find the expression of PPARγprotein increased in RGTZ and CR groups in middle-aged and old rat kidney tissue compared with control group.P53 protein were no obvious different among different groups. Collecting the serum samples of each old rat group,we confirmed the chemical componds and final products of metabolism in the rat serm by HPLC/MS analysis.The results declare that the principle component score was usually distributed in several regions of the scatterplot ellipse graph,and each group has no obvious acrossing.The metabolism products are significantly different among every group.In this study,5 biomarkers were structurally proposed and all these metabolites will provide more information to study the mechanism of preventing rat kidney senescence.In addition,the lipid componds are closely connected with energy and lipid metabolism.It is conceivable that all of the differences observed here investigate that the energy and lipid metabolism in animal have changed much,and perhaps it is the potential reason to induce aging.
All above were summarized as following:PPARγparticipate in the regulating of rat kidney aging.Date further revealed that PPARγagonist enhance the old animal's ability to anti-oxidative stress,reduce the expression of tumor inhibit factor P16. Preventing kidney aging of RGTZ,also provide a better understanding of the role of PPARγ,which can regulate the disorder of lipid metabolism,increase the breakdown of TG,and enhance the sensibility of insulin.
引文
1.Roland Schmitt and Lloyd G.Cantley.The impact of aging on kidney repair.Am J Physiol Renal Physiol.2008;2(20):1099-2027
2.Konrad,Famulski et al.Molecular events in kidney aging.Ourrent Opinion in Nephrology and Hypertension.2005;14:243-248
3.于志恒,白雪源,陈香美,等。肾脏基因表达数据库的建立与肾脏衰老相关基因表达谱研究。中华肾脏病杂志,2001:17(2):135-140
4.JE Martin MT Sheaff.Renal aging.Journal of pathology 2007;211:198-205
5.Robert K.Semple,V.Krishna K.PPARγ and human metabolic disease J.Clin.Invest.2006;(116):581-589
6.Pistrosch F,Herbrig K,Kindel B,et al.Rosiglitazone improves glomerular hyperfiltration,renal endothelial dysfunction,and microalbuminuria of incipient diabetic nephropathy in patients[J].Diabetes,2005;4:2206-2211.
7.McCarthy KJ,Routh RE,Shaw W,et al.Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion[J].Kidney Int,2000;58: 2341-2350.
8.Zheng F,Fomoni A,Elliot SJ,et al.Upregulation of type Ⅰ collagen by TGF-β1 in mesangial cells is blocked by PPAR activation[J].Am J Physiol Renal Physiol,2002;282:F639-F648.
9.Bakris GI,Ruilope LM,McMom SO,et al.Rosiglitazone reduces mieroalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria[J].Hypertens,2006;24:2047-2055.
10.Lee S,Kim W,Kang KP,et al.Agonist of peroxisome proliferator activated receptor γ,rosiglitazone,reduces renal injury and dysfunction in a murine sepsis model[J].Nephrol Dial Transplant,2005;20:1057-1065
11.Gumieniczek A.Effects of the new thiazolidinediOne pioglitazone on development of oxidative stress in liver and kidney of diabetic rabbits[J].Life Sci.2003,74:553-562
12.Villegas,et al.The inflammati on hypothesis of aging:Molecular modulation by calorie restriction.Ann N Y Acad Sci,2001;92A:327-331
1.IssemanI, Green S, Actication of a member of the steroid hormone receptor superfamily by peroxisome proliferators. [J] Kidney Int, 2001; 60: 14-30
2. Michal M. Masternak1 and Andrzej Bartke. PPARs in Calorie Restricted and Genetically Long-LivedMice. [J] 2007; (65): 28436-43
3. Guan YF, Reyer MD . Peroxisome proliferator activated receptorγ is a negative regulator of macrophage activation. [J] Nature, 1998; 391: 79-82
4. ChawlaA, et al. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose predominant expression and induction early in adipocyte differentiation. [J] Endocrinology, 2006; 135: 798-800
5. Tontonoz F, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARgamma2, a ipid-activated transcription factor. [J] Cell 2007; (79) :1147-1156
6. Wahli W, Braissant O, Desvergne B. Peroxisome proliferatoractivated receptors: transcriptional regulators of adipogenesis, lipid metabolism and more .[J] Chemistry & Biology 1995; (2): 261-266
7. Villegas, et al. The inflammation hypothesis of aging: Molecular modulation by calorie restriction.. [J] N Y Acad Sci, 2001; 92A: 327-331
8. JE Martin and MT Shea. Renal ageing. Journal of Pathology [J ] Pathol 2007; 211: 198-205
9. Percy C, Pat B, Poronnik P, Gobe G. Role of oxidative stress in age-associated chronic kidney pathologies. [J] Adv Chron Kidney Dis, 2005; 12(1):78-83.
10. Ma L-J, Fogo AB. Model of robust induction of glomerulosclerosis in mice: importance of genetic background. [J] Kidney Int, 2003; 64: 350-355.
11. Gourtsoyiannis N, Prassopoulos P, Cavouras D, Pantelidis N. The thickness of the renal parenchyma decreases with age: a CT study of 360 patients. [J]Am J Roentgenol 1990; 155 (3):541-544.
12. Nakano M, Ito Y, Kohtani K, Mizuno T, Tauchi H. Age-related change in brush borders of rat kidney cortex. [J] Mech Ageing Dev1985; 33(1): 95-102.
13. Cessac A, Perichon M, Schaeverbeke J, Bakala H. Age-related changes in albumin binding by renal brush border membrane vesicles. Mech Ageing Dev 1993; 70(1-2): 139 -148.
14. Xin Yu, Xiao-Guang Sha.Activation of cerebral peroxisome proliferator-activated receptors gamma exerts neuroprotection by inhibiting oxidative stress following pilocarpine-induced status epilepticus.[J] BRAINRESESARCH12008 (200.): 146-158
15. Lehrke M .Lazar MA.The many faces of PPARgamma. [J] Ceu, 2005; 123(6): 993-999.
16. Von Knethen and Brune, PPARgamma--an important regulator of monocyte/macrophage function. Arch [J] Immunol Exp (Warsz). 2003; 51(4): 219-26.
17. Braissant, B. Desvergne. Diferential expression of peroxisome proliferator -activated receptors (PPARs): Tissue distribution of PPAR-α, -β and -γ in the adult rat. [J] Endocrinology, 1995; (137) 354-366
18. OLIVIER BRAISSANT, et al. Differential Expression of Peroxisome Proliferator-Activated Receptors (PPARs): Tissue Distribution of PPAR-α and PPAR-γ in the Adult Rat. [J] The Endocrine Society 2000; (137):909-921
19. Youfei Guan, Yahua Zhang, Linda Davis and Matthew D. Breyer Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans. [J]Am J Physiol Renal Physiol 1997; (273): 1013-1022,
20. Yu, K.,W. Bayona, C. B. Kallen, H. P. Harding, C. P. Ravera, G. McMahon, M. Brown, and M. A. Lazar. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J. Biol. Chem. 2000; (270): 23975-23983,
21. Heptinstall's Pathology of the Kidney (5th edn), Charles Jeanette J, Olson JL, Schwartz MM, Silva FG (eds). Lippincott-Raven: Philadelphia, New York, 1998.
22. Von Knethen and Brune , PPARgamma-an important regulator of monocyte/macrophage function. Arch Immunol Ther Exp (Warsz). [J] 2003; 51(4):219-26.
23. Bokyung Sung, Seongjoon Park, Byung Pal Yu, et al. Modulation of PPAR in Aging, Inflammation, and Calorie Restriction. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2004; 59: B997-B1006
24. Sohal RS. Oxidative stress hypothesis of aging. [J] Free Radic Biol Med, 2002; 33(5): 573-574
25. Balu, M., Sangeetha. Rejuvenation of antioxidant system in central nervous system of aged rats by grape seed extract. [J] Neurosci. Lett. 2005; 383: 295-300.
26.Bokyung Sung,et al.Amelioration of age-related inflammation and oxidative stress by PPARγ activator:suppression of NF-κB by 2,4-thiazolidinedione.[J]Exp Gerontology,2006;(41):590-599
27.Masoro EJ.et al..Dietary restriction.[J]Exp gerontol,1995;30:291-298
28.Arivazhagan,P.Antioxidant lipoate and tissue antioxidants in aged rats.J.Nutr.Biochem.2000;(11):122-127.
29.Yoo HY,Chang MS,Rho HM.Induction of t he rat Cu/Zn superoxide dismutase gene throught he peroxisome proliferati2 or 2responsive element by arachidonic acid[J]Gene,1999;234:87291.
30.Von Knethen and Brune,PPARgamma-an important regulator of monocyte/macrophage function.Arch Immunol Ther Exp(Warsz).2003;51(4):219-26.
31.Arivazhagan,P.,Panneerseivam,C,Effect of DL-a-lipoic acid on neural antioxidants in aged rats.Pharmacol.Res.2000;42(3):219-222.
1.Gervois P,Torra IP,Fruchart JC,et al.Kidney diease and insulin resistance-clinical impact of thiazolidinedione compounds for kidney disease.[J]Nippon Rinsho,2000;58(2):440-5.
2.Chung HY,Kim H J,Kim KW,et al.Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction.[J]Microsc Res Tech.2002;59:264-272.
3.Asano T,Wakisaka M,Yoshinari M,et al.Peroxisome proliferator-activated receptor gamma 1(PPARgammal) expresses in rat mesangial cells and PPARgamma agonists modulate its differentiation.[J]Biochim Biophys Acta,2000;1497(1):148-54
4.Miles PD,Barak Y,Evans RM,et al.Effect of heterozygous PPARgamma deficiency and TZD treatmeng on insulin resistance associated with age and high-fat feeding.[J]Am J Physiol Endocrinol Metab,2003;284(3):E618-26
5.Deeb SS,Fajas L,Nemoto M,et al.Substitution in PPARgamma2 associated receptor activity, lower body mass index and improved insulin sensitivity. [J] Nat Genet, 1998; 20(3): 284-7.
6. Hayflic L. Intracellular deterninents of cell aging. [J] Mech.Ageing.1984; (12) 28: 177-187
7. Gonzalez, S. et al. Oncogenic activity of Cdc6 through repression of the INK4/ARF locus, [j] Nature, 2006; (440): 702-706
8. Moller DE, Berger JP. Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. International Journal of Obesity[J] 2003; 27(suppl 3): S17-S21.
9. Corton JC, Brown-Borg HM.. Peroxisome proliferator-activated receptor y coactivator 1 in caloric restriction and other models of longevity. [J] Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2005; 60(12): 1494-1509.
10. Stumvoll M, Haring HU. Glitazones: clinical effects and molecular mechanisms EJ1. Ann Med, 2002; 34: 217-224.
11. Fujiwara T, Yoshioka S, Yoshioka T, et al. Characterization of new oral antidiabetic agent CS-045: studies in KK and ob / ob mice and Zucker fatty rats. [J] Diabetes, 1988; 37: 1549-558.
12. Schwartz S. Raskin P, Fonseca V, et al. Effects of troglitazone in insulin-treated patients with type I idiabetes mellitus: Troglitazone and exogenous Insulin Study Group. [J] N Engl J Med, 1998; 338: 861-866.
13. Kurtz Tw. New treatment strategies for patients with hypertension and insulin resistance. [J] Am J Med, 2006; 119: 24-30.
14. Derosa G, Cicero AF, Dangelo A, et al. Thiazolidinedione effects on blood pressure in diabetic patients with metabolic syndrome treated with glimepiride. [J] Hypertens Res, 2005; 28: 91 7-924
15. YueTl, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, et al. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone . [J] circulation 2001; 104: 2588-94
16. Sung B, Park S, Yu BP, Chung HY. Modulation of PPAR in aging, inflammation, and calorie restriction. [J] Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2004; 59(10): 997-1006.
17. Bara Y, Nelson MC, Ong ES, et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. [J] MolCell, 1999; 4:585-595
18. Lapsys,et al. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. [J] Arterioscler Thromb Vasc Biol. 2002; 22: 717-726
19. Kritchevsky et al. Influence on chornic intake on experiment carcinogenesisl. [J] Adv Exp Blot, 1986; 206-255.
20. Guan Y, Breyer MD. Peroxisome proliferator-activated receptors (PPARs) : novel therapeutic targets in renal diease, kidney Int 2001; 60: 14-30
21. Anette Melk. Cell senescence in growth and aging of rat kidneys. Kidney International, Vol. 2003 (63); 2134-2143
22. Janakiraman Krishnamurthy, Chad Torrice, et al. Ink4a/Arf expression is a biomarker of aging. [J] Clin. Invest. 2004 ; (114): 1299-1307
23. Bandyopadhyay D, Timchenko N, Suwa T, et al. The human melanocyte : a model system to study the complexity of cellular aging and transformation in non-fibroblastic cells . [J] Exp Gerontol, 2001 ;36 ( 8 ): 1265-1275
24. Noble JR, Zhong Z-H, Neumann AA, Melki JR, Clark SJ, Reddel RR. Alerations in the p16 and p53 tumor suppressor genes of hTERT-immortalized human fibroblasts. Oncogene. 2004;( 23): 3116-3121
25. Munro J, Barr NI, Ireland H, Morrison V, and Parkinson EK. Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock.[J] Exp Cell Res 2004; 295: 525-538
26. Maier, B., Gluba, W., Bernier, et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, Science 2004; (299): 1355-1359.
27. Rincon, Muzumdar, Atzmon, et al. Long-term molecular and cellular stability of human neural stem cell lines. [J] Exp. Cell Res.2004; ( 294):559-570
28. Krishnamurthy, J., Torrice, C., et al. Ink4a/Arf expression is induced by oncogenic ras and is a biomarker of aging.[J.] Clin. Invest. 2004; (114): 1299-1307.
29. Anette Melk, Cell senescence in growth and aging of rat kidneys. [J] Kidney International, Vol. 2003 (63), 2134-2143
30.KNETHEN,BrunB.Delayed activation of PPARgamma by LPS and EFN-gamma attenuates the oxidative brust in macrophages[J]FASEBJ.2001;(15):535-544
31.Wang Z,Al-Regaiey KA,Mastemak MM,Bartke A.Adipocytokinesand lipid levels in Ames dwarf and calorie-restricted mice.Journals of Gerontology - Series A Biological Sciences andMedical Sciences.[J]2006;61(4):323-331.
32.郑文婕,童坦君,张宗玉。细胞衰老的重要通路:P16~(NK4a)/Rb和P19~(ARF)/P53/P21~(Cip1)。生命的化学.2002;(22)4:314-316
33.Sohal RS.Oxidative stress hypothesis of aging.[J]Free Radic Biol Med,2002;33(5):573-574
34.KatoK,Satoh H,Endo Y,et al.Thiazolidinediones down-rgulates plasminogen activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway.[J]Circ Res,1999;85(5):394-402
35.Bull,Steffensen,K.R.Leers.Activation of PPAR gamma in colon tumor cell lines by oxidized metabolites of linoleic acid,endogenous ligands for PPAR gamma.[J]Carcinogenesis2003;(24):1717-1722.
36.Cuzzocrea S,Pisano B,Dugl L,et al.Rosiglitazone,a ligand of the peroxisome proliferator-aceivated receptor-gamma,reduces acute inflammation.[J]Eru,2004;483(1):79-93
37.Chinetti G,F ruchart JC,Staels B.Peroxisome proliferator-activated receptors(PPARS):nuclear receptors at the crossroads between lipid.metabolism and inflammation.[J]Inflamm Res,2000;49(10):497-505
38.L J,Marcantoni C,Linton MF,et al.Peroxisome proliferator-activated receptor-gamma agonist trolitazone protects against nondiabetic glomerulosclerosis in rats.Kidney Int,2001;59(5):1899-910
39.Zhou,Y.C.& Waxman,D.J.Cross-talk between janus kinasesignal transducer activator of transcription(JAK-STAT) and peroxisome prolifera Proliferator -activated receptor(PPAR) signaling pathways.[J]Biol Chem 1999;(274):2672-2681.
40.Delerive,P.,Martin-Nizard,F.,Chinetti,G.,Trottein,F,Fruchart,J.C.PPAR activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial ceils by inhibiting the AP-1 signaling pathway.Circ.Res.[J]1999;(85): 394-402.
41.Roland Schmitt,Lloyd G.The impact of aging on kidney repair.[J]Am J Physiol Renal Physiol.2008;Februar(20):1099-2027
42.Bara Y,Nelson MC,Ong ES,et al.PPAR gamma is required for placental,cardiac,and adipose tissue development.[J]MolCell,1999;(4):585-595
1.Magalhaes JP,Costa J.The Human Ageing Genomic Resources.[J]Nucleic Acids Research,2005;33:D537-D543
2.Famulski KS and Halloran PF.Molecular events in kidney ageing.[J]Curr OpinNephrol Hypertens,2005;14:243-248
3.Sabatine MS,Liu E,Morrow DA,Heller E,McCarroll R,Wiegand R,et al.[J]Metabolomic identification of novel biomarkers of myocardial ischemia.Circulation 2005;112:3868-3875
4.Soga T,Baran R,Suematsu M,Ueno Y,Ikeda S,Sakurakawa T,et al.Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption.[J]Bioi Chem 2006;281:16768-16776
5.Bijlsma S,Bobeldijk I,Verheij ER,Ramaker R,Kochhar S,Macdonald IA,et al.Large-scale human metabolomics studies:a strategy for data(pre-) processing and validation.[J]Anal Chem 2006;78:567-574.
6.Nicholson JK,Lindon JC,Holmes E.'Metabonomics':understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.[J]Xenobiotica 1999;29:1181-1189.
7.Ravussin E.Smith SR.Increased fat intake,impaired fat oxidation and failure of fat cell proliferation result in ectopic fat storage,insulin resistance,and type 2 diabetes mellitus.[J]Ann NY Acad Sci,2002;967:363-378.
8.Cheng H L,M ostoslavsky R.Developmental defects and p53 hyperacetylation in Sir2homolog(SIRT) deficient mice.[J]Proc Natl Acad Sci USA,2003;100:10794-10799.
9.Holzenberger M,Dupont J,Ducos B,et al.IGF 1 receptor regulates lifespan and resistance to oxidative stress in mice.[J]Nature,2003;421:182-187.
10.Auwerx J,et al.The ultimate thrifty gene.[J]Diabetologia.1999;42:1033-1049.
11.张秀锦,叶平,王兆君.衰老后PPAR γ目标基因表达的改变与胰岛素抵抗的关系。中华老年医学2004:1:(24)56-67
12.McGarry JD,Banting lecture.Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.[J]Diabetes,2002;3,7-18.
13.Pan DA,Lillioja S,Kriketos AD,et al.Skeletal muscle triglyceride levels are inversely related to insulin action.[J]Diabetes,1997;983-988.
14.Masoro EJ.Dietary restriction.[J]Exp Gerontol,1995;30:291-298
1.Terasaki PI,Cecka JM,Gjertson DW.Impact analysis:a method for evaluating the impact of factors in clinical renal transplantation.In:Cecka JM,Terasaki PI,eds.Clinical Transplants.UCLA Tissue Typing Laboratory,Los Angeles,CA:1998;437-441
2.Lindeman RD,Tobin J,Shock NW.longitudinal studies on the rate of decline in renal function with age.J Am Geriatr Soc 1985;33:278-285
3.Hayflick L,Moorhead PS.The serial cultivation of human diploid cell strains.Exp Cell Res 1961;25:585-621
4.GourtsoyiannisN,Prassopoulos P,Cavouras D,Pantelidis N.The thickness of the renal parenchyma decreases with age.ACT study of the 360 patients Am J Roentgenol 1990;155:541-544.
5.Lindeman RD,Goldman R.Anatomic and physiololgic age changes in kidney.Exp Gerontol 1986;21:379-406
6.Cockcroft DW,Gault MH.Prediction of creatinine clearance from serum creatinine.Nephron 1976;16:31-41
7.Levey AS,Bosch JP,Lewis JB et al.A more accurate method to estimate glomerular filtration rate from serum creatinine:a new prediction equation.Modification of Diet in Renal Disease Study Group.Ann Intem Med 1999;130:461-470
8.Lindeman RD,Tobin J,Shock NW.Longitudinal studies on the rate of decline in renal function with age.J Am Geriatr Soc 1985;33:278-285
9.Fliser D,Franek E,Joest Met al.Renal function in the elderly:impact of hypertension and cardiac function.Kidney Int 1997;51:1196-1204
10.Pannu N,Halloran PF.The kidney in aging.In:Greenberg A,ed.Primer on Kidney Diseases.Academic Press,San Diego,CA:2001;377-381
11 .Melk A, Ramassar V, Helms LM et al. Telomere shortening in kidneys with age. J Am Soc Nephrol 2000; 11: 444-453
12.Melk A, Kittikowit W, Sandhu I et al. Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int 2003; 63: 2134-2143
13.Melk A, Rayner D, Pehowich ED, Solez K, Halloran PF. Renal senescence reflects different mechanisms in human and rodent kidneys. J Am Soc Nephrol 2001; 12: 616A-617A.
14.Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995; 81: 323-330
15.Serrano M, Lee H-W, Chin L et al. Role of the INK4a locus in tumor suppressor and cell mortality. Cell 1996; 85: 27-37
16.Ramirez RD, Morales CP, Herbert BS et al. Putative telomereindependent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev 2001; 15:398-403
17.Haber DA. Splicing into senescence: the curious case of p16 and p19ARF. Cell 1997; 91:555-558
18. Duan JM , Zhang ZY, Tong TJ. Senescence delay of human diploid fibroblast induced by antisense p161NK4a expression. J Biol Chem. 2001; 276(51): 483-525
19. Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 2001; 413: 83-86
20. Melk A, Schmidt BMW, Takeuchi O et al. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int 2003; 213: 61-70
21. Melk A, Kittikowit W, Sandhu I et al. Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int 2003; 63: 2134-2143.
22. Melk A, Rayner D, Pehowich ED, Solez K, Halloran PF. Renal senescence reflects different mechanisms in human and rodent kidneys. J Am Soc Nephrol 2001; 12: 616A-617A
23. Rudolph KL, Chang S, Millard M, Schreiber-Agus N, DePinho RA. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 2000; 287: 1253-1258.
24. Melk A, Halloran PF, Sarwal M. Gene expression pattern in human renal senescence using microarray technique. Am J Transplant 2002; 2: 383
25. Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescenceassociated-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 2000; 113: 3613-3622
26. Dimri GP, Lee X, Basile G et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92: 9363-9367
27. Sitte N, Merker K, Grune T, von Zglinicki T. Lipofuscin accumulation in proliferating fibroblasts in vitro: an indicatorof oxidative stress. Exp Gerontol 2001; 36: 475-486
28. Melk A, Kittikowit W, Sandhu I et al. Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int 2003; 63: 2134-2143
29. Lindeman RD, Goldman R. Anatomic and physiologic age changes in the kidney. Exp Gerontol 1986; 21: 379-406
30. Fliser D, Zeier M, Nowack R, Ritz E. Renal functional reserve in healthy elderly subjects. J Am Soc Nephrol 1993; 3: 1371-1377
31. Melk A, Schmidt BMW, Takeuchi O, Urmson J, Halloran PF. Senescence marker p16INK4a is induced in acute rejection: evidence that rejection induces epithelial cell senescence. Am J Transplant 2003; 5: 542.
32. Melk A, Schmidt BMW, Urmson J, Solez K, Halloran PF. Does donor age affect immunogenicity or tissue fragility? Evidence that old kidneys develop equivalent inflammation but more tubulitis and tubular atrophy. Am J Transplant 2003; 5: 542
33. Lunz JG, III, Contrucci S, Ruppert K et al. Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs. Am J Pathol 2001; 158: 1379-1390
34. Melk A, Kittikowit W, Sandhu I et al. Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int 2003; 63: 2134-2143
35.Melk A,Rayner D,Pehowich ED,Solez K,Halloran PF.Renal senescence reflects different mechanisms in human and rodent kidneys.J Am Soc Nephrol 2001;12:616A-617A.
36.Joosten SA,Van Ham V,Nolan CE et al.Telomere shortening and cellular senescence in a model of chronic renal allografl rejection.Am J Pathol 2003;162:1305-1312
37.Chang E,Harley CB.Telomere length and replicative aging in human vascular tissues.Proc Natl Acad Sci USA 1995;92:11190-11194
2.Konrad,Famulski et al.Molecular events in kidney aging.Ourrent Opinion in Nephrology and Hypertension.2005;14:243-248
3.于志恒,白雪源,陈香美,等。肾脏基因表达数据库的建立与肾脏衰老相关基因表达谱研究。中华肾脏病杂志,2001:17(2):135-140
4.JE Martin MT Sheaff.Renal aging.Journal of pathology 2007;211:198-205
5.Robert K.Semple,V.Krishna K.PPARγ and human metabolic disease J.Clin.Invest.2006;(116):581-589
6.Pistrosch F,Herbrig K,Kindel B,et al.Rosiglitazone improves glomerular hyperfiltration,renal endothelial dysfunction,and microalbuminuria of incipient diabetic nephropathy in patients[J].Diabetes,2005;4:2206-2211.
7.McCarthy KJ,Routh RE,Shaw W,et al.Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion[J].Kidney Int,2000;58: 2341-2350.
8.Zheng F,Fomoni A,Elliot SJ,et al.Upregulation of type Ⅰ collagen by TGF-β1 in mesangial cells is blocked by PPAR activation[J].Am J Physiol Renal Physiol,2002;282:F639-F648.
9.Bakris GI,Ruilope LM,McMom SO,et al.Rosiglitazone reduces mieroalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria[J].Hypertens,2006;24:2047-2055.
10.Lee S,Kim W,Kang KP,et al.Agonist of peroxisome proliferator activated receptor γ,rosiglitazone,reduces renal injury and dysfunction in a murine sepsis model[J].Nephrol Dial Transplant,2005;20:1057-1065
11.Gumieniczek A.Effects of the new thiazolidinediOne pioglitazone on development of oxidative stress in liver and kidney of diabetic rabbits[J].Life Sci.2003,74:553-562
12.Villegas,et al.The inflammati on hypothesis of aging:Molecular modulation by calorie restriction.Ann N Y Acad Sci,2001;92A:327-331
1.IssemanI, Green S, Actication of a member of the steroid hormone receptor superfamily by peroxisome proliferators. [J] Kidney Int, 2001; 60: 14-30
2. Michal M. Masternak1 and Andrzej Bartke. PPARs in Calorie Restricted and Genetically Long-LivedMice. [J] 2007; (65): 28436-43
3. Guan YF, Reyer MD . Peroxisome proliferator activated receptorγ is a negative regulator of macrophage activation. [J] Nature, 1998; 391: 79-82
4. ChawlaA, et al. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose predominant expression and induction early in adipocyte differentiation. [J] Endocrinology, 2006; 135: 798-800
5. Tontonoz F, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARgamma2, a ipid-activated transcription factor. [J] Cell 2007; (79) :1147-1156
6. Wahli W, Braissant O, Desvergne B. Peroxisome proliferatoractivated receptors: transcriptional regulators of adipogenesis, lipid metabolism and more .[J] Chemistry & Biology 1995; (2): 261-266
7. Villegas, et al. The inflammation hypothesis of aging: Molecular modulation by calorie restriction.. [J] N Y Acad Sci, 2001; 92A: 327-331
8. JE Martin and MT Shea. Renal ageing. Journal of Pathology [J ] Pathol 2007; 211: 198-205
9. Percy C, Pat B, Poronnik P, Gobe G. Role of oxidative stress in age-associated chronic kidney pathologies. [J] Adv Chron Kidney Dis, 2005; 12(1):78-83.
10. Ma L-J, Fogo AB. Model of robust induction of glomerulosclerosis in mice: importance of genetic background. [J] Kidney Int, 2003; 64: 350-355.
11. Gourtsoyiannis N, Prassopoulos P, Cavouras D, Pantelidis N. The thickness of the renal parenchyma decreases with age: a CT study of 360 patients. [J]Am J Roentgenol 1990; 155 (3):541-544.
12. Nakano M, Ito Y, Kohtani K, Mizuno T, Tauchi H. Age-related change in brush borders of rat kidney cortex. [J] Mech Ageing Dev1985; 33(1): 95-102.
13. Cessac A, Perichon M, Schaeverbeke J, Bakala H. Age-related changes in albumin binding by renal brush border membrane vesicles. Mech Ageing Dev 1993; 70(1-2): 139 -148.
14. Xin Yu, Xiao-Guang Sha.Activation of cerebral peroxisome proliferator-activated receptors gamma exerts neuroprotection by inhibiting oxidative stress following pilocarpine-induced status epilepticus.[J] BRAINRESESARCH12008 (200.): 146-158
15. Lehrke M .Lazar MA.The many faces of PPARgamma. [J] Ceu, 2005; 123(6): 993-999.
16. Von Knethen and Brune, PPARgamma--an important regulator of monocyte/macrophage function. Arch [J] Immunol Exp (Warsz). 2003; 51(4): 219-26.
17. Braissant, B. Desvergne. Diferential expression of peroxisome proliferator -activated receptors (PPARs): Tissue distribution of PPAR-α, -β and -γ in the adult rat. [J] Endocrinology, 1995; (137) 354-366
18. OLIVIER BRAISSANT, et al. Differential Expression of Peroxisome Proliferator-Activated Receptors (PPARs): Tissue Distribution of PPAR-α and PPAR-γ in the Adult Rat. [J] The Endocrine Society 2000; (137):909-921
19. Youfei Guan, Yahua Zhang, Linda Davis and Matthew D. Breyer Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans. [J]Am J Physiol Renal Physiol 1997; (273): 1013-1022,
20. Yu, K.,W. Bayona, C. B. Kallen, H. P. Harding, C. P. Ravera, G. McMahon, M. Brown, and M. A. Lazar. Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J. Biol. Chem. 2000; (270): 23975-23983,
21. Heptinstall's Pathology of the Kidney (5th edn), Charles Jeanette J, Olson JL, Schwartz MM, Silva FG (eds). Lippincott-Raven: Philadelphia, New York, 1998.
22. Von Knethen and Brune , PPARgamma-an important regulator of monocyte/macrophage function. Arch Immunol Ther Exp (Warsz). [J] 2003; 51(4):219-26.
23. Bokyung Sung, Seongjoon Park, Byung Pal Yu, et al. Modulation of PPAR in Aging, Inflammation, and Calorie Restriction. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2004; 59: B997-B1006
24. Sohal RS. Oxidative stress hypothesis of aging. [J] Free Radic Biol Med, 2002; 33(5): 573-574
25. Balu, M., Sangeetha. Rejuvenation of antioxidant system in central nervous system of aged rats by grape seed extract. [J] Neurosci. Lett. 2005; 383: 295-300.
26.Bokyung Sung,et al.Amelioration of age-related inflammation and oxidative stress by PPARγ activator:suppression of NF-κB by 2,4-thiazolidinedione.[J]Exp Gerontology,2006;(41):590-599
27.Masoro EJ.et al..Dietary restriction.[J]Exp gerontol,1995;30:291-298
28.Arivazhagan,P.Antioxidant lipoate and tissue antioxidants in aged rats.J.Nutr.Biochem.2000;(11):122-127.
29.Yoo HY,Chang MS,Rho HM.Induction of t he rat Cu/Zn superoxide dismutase gene throught he peroxisome proliferati2 or 2responsive element by arachidonic acid[J]Gene,1999;234:87291.
30.Von Knethen and Brune,PPARgamma-an important regulator of monocyte/macrophage function.Arch Immunol Ther Exp(Warsz).2003;51(4):219-26.
31.Arivazhagan,P.,Panneerseivam,C,Effect of DL-a-lipoic acid on neural antioxidants in aged rats.Pharmacol.Res.2000;42(3):219-222.
1.Gervois P,Torra IP,Fruchart JC,et al.Kidney diease and insulin resistance-clinical impact of thiazolidinedione compounds for kidney disease.[J]Nippon Rinsho,2000;58(2):440-5.
2.Chung HY,Kim H J,Kim KW,et al.Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction.[J]Microsc Res Tech.2002;59:264-272.
3.Asano T,Wakisaka M,Yoshinari M,et al.Peroxisome proliferator-activated receptor gamma 1(PPARgammal) expresses in rat mesangial cells and PPARgamma agonists modulate its differentiation.[J]Biochim Biophys Acta,2000;1497(1):148-54
4.Miles PD,Barak Y,Evans RM,et al.Effect of heterozygous PPARgamma deficiency and TZD treatmeng on insulin resistance associated with age and high-fat feeding.[J]Am J Physiol Endocrinol Metab,2003;284(3):E618-26
5.Deeb SS,Fajas L,Nemoto M,et al.Substitution in PPARgamma2 associated receptor activity, lower body mass index and improved insulin sensitivity. [J] Nat Genet, 1998; 20(3): 284-7.
6. Hayflic L. Intracellular deterninents of cell aging. [J] Mech.Ageing.1984; (12) 28: 177-187
7. Gonzalez, S. et al. Oncogenic activity of Cdc6 through repression of the INK4/ARF locus, [j] Nature, 2006; (440): 702-706
8. Moller DE, Berger JP. Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. International Journal of Obesity[J] 2003; 27(suppl 3): S17-S21.
9. Corton JC, Brown-Borg HM.. Peroxisome proliferator-activated receptor y coactivator 1 in caloric restriction and other models of longevity. [J] Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2005; 60(12): 1494-1509.
10. Stumvoll M, Haring HU. Glitazones: clinical effects and molecular mechanisms EJ1. Ann Med, 2002; 34: 217-224.
11. Fujiwara T, Yoshioka S, Yoshioka T, et al. Characterization of new oral antidiabetic agent CS-045: studies in KK and ob / ob mice and Zucker fatty rats. [J] Diabetes, 1988; 37: 1549-558.
12. Schwartz S. Raskin P, Fonseca V, et al. Effects of troglitazone in insulin-treated patients with type I idiabetes mellitus: Troglitazone and exogenous Insulin Study Group. [J] N Engl J Med, 1998; 338: 861-866.
13. Kurtz Tw. New treatment strategies for patients with hypertension and insulin resistance. [J] Am J Med, 2006; 119: 24-30.
14. Derosa G, Cicero AF, Dangelo A, et al. Thiazolidinedione effects on blood pressure in diabetic patients with metabolic syndrome treated with glimepiride. [J] Hypertens Res, 2005; 28: 91 7-924
15. YueTl, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, et al. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone . [J] circulation 2001; 104: 2588-94
16. Sung B, Park S, Yu BP, Chung HY. Modulation of PPAR in aging, inflammation, and calorie restriction. [J] Journals of Gerontology - Series A Biological Sciences and Medical Sciences. 2004; 59(10): 997-1006.
17. Bara Y, Nelson MC, Ong ES, et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. [J] MolCell, 1999; 4:585-595
18. Lapsys,et al. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. [J] Arterioscler Thromb Vasc Biol. 2002; 22: 717-726
19. Kritchevsky et al. Influence on chornic intake on experiment carcinogenesisl. [J] Adv Exp Blot, 1986; 206-255.
20. Guan Y, Breyer MD. Peroxisome proliferator-activated receptors (PPARs) : novel therapeutic targets in renal diease, kidney Int 2001; 60: 14-30
21. Anette Melk. Cell senescence in growth and aging of rat kidneys. Kidney International, Vol. 2003 (63); 2134-2143
22. Janakiraman Krishnamurthy, Chad Torrice, et al. Ink4a/Arf expression is a biomarker of aging. [J] Clin. Invest. 2004 ; (114): 1299-1307
23. Bandyopadhyay D, Timchenko N, Suwa T, et al. The human melanocyte : a model system to study the complexity of cellular aging and transformation in non-fibroblastic cells . [J] Exp Gerontol, 2001 ;36 ( 8 ): 1265-1275
24. Noble JR, Zhong Z-H, Neumann AA, Melki JR, Clark SJ, Reddel RR. Alerations in the p16 and p53 tumor suppressor genes of hTERT-immortalized human fibroblasts. Oncogene. 2004;( 23): 3116-3121
25. Munro J, Barr NI, Ireland H, Morrison V, and Parkinson EK. Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock.[J] Exp Cell Res 2004; 295: 525-538
26. Maier, B., Gluba, W., Bernier, et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, Science 2004; (299): 1355-1359.
27. Rincon, Muzumdar, Atzmon, et al. Long-term molecular and cellular stability of human neural stem cell lines. [J] Exp. Cell Res.2004; ( 294):559-570
28. Krishnamurthy, J., Torrice, C., et al. Ink4a/Arf expression is induced by oncogenic ras and is a biomarker of aging.[J.] Clin. Invest. 2004; (114): 1299-1307.
29. Anette Melk, Cell senescence in growth and aging of rat kidneys. [J] Kidney International, Vol. 2003 (63), 2134-2143
30.KNETHEN,BrunB.Delayed activation of PPARgamma by LPS and EFN-gamma attenuates the oxidative brust in macrophages[J]FASEBJ.2001;(15):535-544
31.Wang Z,Al-Regaiey KA,Mastemak MM,Bartke A.Adipocytokinesand lipid levels in Ames dwarf and calorie-restricted mice.Journals of Gerontology - Series A Biological Sciences andMedical Sciences.[J]2006;61(4):323-331.
32.郑文婕,童坦君,张宗玉。细胞衰老的重要通路:P16~(NK4a)/Rb和P19~(ARF)/P53/P21~(Cip1)。生命的化学.2002;(22)4:314-316
33.Sohal RS.Oxidative stress hypothesis of aging.[J]Free Radic Biol Med,2002;33(5):573-574
34.KatoK,Satoh H,Endo Y,et al.Thiazolidinediones down-rgulates plasminogen activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway.[J]Circ Res,1999;85(5):394-402
35.Bull,Steffensen,K.R.Leers.Activation of PPAR gamma in colon tumor cell lines by oxidized metabolites of linoleic acid,endogenous ligands for PPAR gamma.[J]Carcinogenesis2003;(24):1717-1722.
36.Cuzzocrea S,Pisano B,Dugl L,et al.Rosiglitazone,a ligand of the peroxisome proliferator-aceivated receptor-gamma,reduces acute inflammation.[J]Eru,2004;483(1):79-93
37.Chinetti G,F ruchart JC,Staels B.Peroxisome proliferator-activated receptors(PPARS):nuclear receptors at the crossroads between lipid.metabolism and inflammation.[J]Inflamm Res,2000;49(10):497-505
38.L J,Marcantoni C,Linton MF,et al.Peroxisome proliferator-activated receptor-gamma agonist trolitazone protects against nondiabetic glomerulosclerosis in rats.Kidney Int,2001;59(5):1899-910
39.Zhou,Y.C.& Waxman,D.J.Cross-talk between janus kinasesignal transducer activator of transcription(JAK-STAT) and peroxisome prolifera Proliferator -activated receptor(PPAR) signaling pathways.[J]Biol Chem 1999;(274):2672-2681.
40.Delerive,P.,Martin-Nizard,F.,Chinetti,G.,Trottein,F,Fruchart,J.C.PPAR activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial ceils by inhibiting the AP-1 signaling pathway.Circ.Res.[J]1999;(85): 394-402.
41.Roland Schmitt,Lloyd G.The impact of aging on kidney repair.[J]Am J Physiol Renal Physiol.2008;Februar(20):1099-2027
42.Bara Y,Nelson MC,Ong ES,et al.PPAR gamma is required for placental,cardiac,and adipose tissue development.[J]MolCell,1999;(4):585-595
1.Magalhaes JP,Costa J.The Human Ageing Genomic Resources.[J]Nucleic Acids Research,2005;33:D537-D543
2.Famulski KS and Halloran PF.Molecular events in kidney ageing.[J]Curr OpinNephrol Hypertens,2005;14:243-248
3.Sabatine MS,Liu E,Morrow DA,Heller E,McCarroll R,Wiegand R,et al.[J]Metabolomic identification of novel biomarkers of myocardial ischemia.Circulation 2005;112:3868-3875
4.Soga T,Baran R,Suematsu M,Ueno Y,Ikeda S,Sakurakawa T,et al.Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption.[J]Bioi Chem 2006;281:16768-16776
5.Bijlsma S,Bobeldijk I,Verheij ER,Ramaker R,Kochhar S,Macdonald IA,et al.Large-scale human metabolomics studies:a strategy for data(pre-) processing and validation.[J]Anal Chem 2006;78:567-574.
6.Nicholson JK,Lindon JC,Holmes E.'Metabonomics':understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data.[J]Xenobiotica 1999;29:1181-1189.
7.Ravussin E.Smith SR.Increased fat intake,impaired fat oxidation and failure of fat cell proliferation result in ectopic fat storage,insulin resistance,and type 2 diabetes mellitus.[J]Ann NY Acad Sci,2002;967:363-378.
8.Cheng H L,M ostoslavsky R.Developmental defects and p53 hyperacetylation in Sir2homolog(SIRT) deficient mice.[J]Proc Natl Acad Sci USA,2003;100:10794-10799.
9.Holzenberger M,Dupont J,Ducos B,et al.IGF 1 receptor regulates lifespan and resistance to oxidative stress in mice.[J]Nature,2003;421:182-187.
10.Auwerx J,et al.The ultimate thrifty gene.[J]Diabetologia.1999;42:1033-1049.
11.张秀锦,叶平,王兆君.衰老后PPAR γ目标基因表达的改变与胰岛素抵抗的关系。中华老年医学2004:1:(24)56-67
12.McGarry JD,Banting lecture.Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.[J]Diabetes,2002;3,7-18.
13.Pan DA,Lillioja S,Kriketos AD,et al.Skeletal muscle triglyceride levels are inversely related to insulin action.[J]Diabetes,1997;983-988.
14.Masoro EJ.Dietary restriction.[J]Exp Gerontol,1995;30:291-298
1.Terasaki PI,Cecka JM,Gjertson DW.Impact analysis:a method for evaluating the impact of factors in clinical renal transplantation.In:Cecka JM,Terasaki PI,eds.Clinical Transplants.UCLA Tissue Typing Laboratory,Los Angeles,CA:1998;437-441
2.Lindeman RD,Tobin J,Shock NW.longitudinal studies on the rate of decline in renal function with age.J Am Geriatr Soc 1985;33:278-285
3.Hayflick L,Moorhead PS.The serial cultivation of human diploid cell strains.Exp Cell Res 1961;25:585-621
4.GourtsoyiannisN,Prassopoulos P,Cavouras D,Pantelidis N.The thickness of the renal parenchyma decreases with age.ACT study of the 360 patients Am J Roentgenol 1990;155:541-544.
5.Lindeman RD,Goldman R.Anatomic and physiololgic age changes in kidney.Exp Gerontol 1986;21:379-406
6.Cockcroft DW,Gault MH.Prediction of creatinine clearance from serum creatinine.Nephron 1976;16:31-41
7.Levey AS,Bosch JP,Lewis JB et al.A more accurate method to estimate glomerular filtration rate from serum creatinine:a new prediction equation.Modification of Diet in Renal Disease Study Group.Ann Intem Med 1999;130:461-470
8.Lindeman RD,Tobin J,Shock NW.Longitudinal studies on the rate of decline in renal function with age.J Am Geriatr Soc 1985;33:278-285
9.Fliser D,Franek E,Joest Met al.Renal function in the elderly:impact of hypertension and cardiac function.Kidney Int 1997;51:1196-1204
10.Pannu N,Halloran PF.The kidney in aging.In:Greenberg A,ed.Primer on Kidney Diseases.Academic Press,San Diego,CA:2001;377-381
11 .Melk A, Ramassar V, Helms LM et al. Telomere shortening in kidneys with age. J Am Soc Nephrol 2000; 11: 444-453
12.Melk A, Kittikowit W, Sandhu I et al. Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int 2003; 63: 2134-2143
13.Melk A, Rayner D, Pehowich ED, Solez K, Halloran PF. Renal senescence reflects different mechanisms in human and rodent kidneys. J Am Soc Nephrol 2001; 12: 616A-617A.
14.Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995; 81: 323-330
15.Serrano M, Lee H-W, Chin L et al. Role of the INK4a locus in tumor suppressor and cell mortality. Cell 1996; 85: 27-37
16.Ramirez RD, Morales CP, Herbert BS et al. Putative telomereindependent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev 2001; 15:398-403
17.Haber DA. Splicing into senescence: the curious case of p16 and p19ARF. Cell 1997; 91:555-558
18. Duan JM , Zhang ZY, Tong TJ. Senescence delay of human diploid fibroblast induced by antisense p161NK4a expression. J Biol Chem. 2001; 276(51): 483-525
19. Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 2001; 413: 83-86
20. Melk A, Schmidt BMW, Takeuchi O et al. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int 2003; 213: 61-70
21. Melk A, Kittikowit W, Sandhu I et al. Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int 2003; 63: 2134-2143.
22. Melk A, Rayner D, Pehowich ED, Solez K, Halloran PF. Renal senescence reflects different mechanisms in human and rodent kidneys. J Am Soc Nephrol 2001; 12: 616A-617A
23. Rudolph KL, Chang S, Millard M, Schreiber-Agus N, DePinho RA. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 2000; 287: 1253-1258.
24. Melk A, Halloran PF, Sarwal M. Gene expression pattern in human renal senescence using microarray technique. Am J Transplant 2002; 2: 383
25. Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescenceassociated-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 2000; 113: 3613-3622
26. Dimri GP, Lee X, Basile G et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92: 9363-9367
27. Sitte N, Merker K, Grune T, von Zglinicki T. Lipofuscin accumulation in proliferating fibroblasts in vitro: an indicatorof oxidative stress. Exp Gerontol 2001; 36: 475-486
28. Melk A, Kittikowit W, Sandhu I et al. Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int 2003; 63: 2134-2143
29. Lindeman RD, Goldman R. Anatomic and physiologic age changes in the kidney. Exp Gerontol 1986; 21: 379-406
30. Fliser D, Zeier M, Nowack R, Ritz E. Renal functional reserve in healthy elderly subjects. J Am Soc Nephrol 1993; 3: 1371-1377
31. Melk A, Schmidt BMW, Takeuchi O, Urmson J, Halloran PF. Senescence marker p16INK4a is induced in acute rejection: evidence that rejection induces epithelial cell senescence. Am J Transplant 2003; 5: 542.
32. Melk A, Schmidt BMW, Urmson J, Solez K, Halloran PF. Does donor age affect immunogenicity or tissue fragility? Evidence that old kidneys develop equivalent inflammation but more tubulitis and tubular atrophy. Am J Transplant 2003; 5: 542
33. Lunz JG, III, Contrucci S, Ruppert K et al. Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs. Am J Pathol 2001; 158: 1379-1390
34. Melk A, Kittikowit W, Sandhu I et al. Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening. Kidney Int 2003; 63: 2134-2143
35.Melk A,Rayner D,Pehowich ED,Solez K,Halloran PF.Renal senescence reflects different mechanisms in human and rodent kidneys.J Am Soc Nephrol 2001;12:616A-617A.
36.Joosten SA,Van Ham V,Nolan CE et al.Telomere shortening and cellular senescence in a model of chronic renal allografl rejection.Am J Pathol 2003;162:1305-1312
37.Chang E,Harley CB.Telomere length and replicative aging in human vascular tissues.Proc Natl Acad Sci USA 1995;92:11190-11194