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中华肾病研究电子杂志 ›› 2013, Vol. 02 ›› Issue (06) : 304 -309. doi: 10.3877/cma.j.issn.2095-3216.2013.06.006

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足细胞损伤信号通路的研究进展
史伟1,2,(), 谈晓凡1,2, 赵星辰1,2, 陈源汉1   
  1. 1.510080 广州,广东省人民医院,广东省医学科学院
    2.南方医科大学
  • 出版日期:2013-12-15
  • 通信作者: 史伟
  • 基金资助:
    国家自然科学基金项目(81270784)国家临床重点专科建设项目

Update on signaling pathways of podocyte injury

Wei SHI1,(), Xiao-fan TAN1, Xing-chen ZHAO1, Yuan-han CHEN1   

  1. 1.Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
  • Published:2013-12-15
  • Corresponding author: Wei SHI
引用本文:

史伟, 谈晓凡, 赵星辰, 陈源汉. 足细胞损伤信号通路的研究进展[J/OL]. 中华肾病研究电子杂志, 2013, 02(06): 304-309.

Wei SHI, Xiao-fan TAN, Xing-chen ZHAO, Yuan-han CHEN. Update on signaling pathways of podocyte injury[J/OL]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2013, 02(06): 304-309.

足细胞是位于肾小球基底膜外侧的高度分化的细胞,有高度的结构和功能特异性,在维持肾小球滤过膜的结构和功能上起着重要作用。 研究发现足细胞损伤是介导肾小球疾病进展的关键因素,以足细胞损伤为靶点的治疗现已成为慢性肾脏病治疗的新手段。 目前足细胞损伤机制的研究是肾脏疾病领域的研究热点,足细胞损伤的信号通路为人们深入探索其致病机制提供了重要线索,对信号通路中关键分子的干预可能为治疗足细胞病提供新的方向。 本文主要介绍无翅型MMTV 整合位点家族成员蛋白(Wnt)/β-连环蛋白(β-catenin)、缺刻蛋白(Notch)信号通路,足细胞骨架调控信号通路,转化生长因子-β(TGF-β)/骨形成蛋白(BMP-7)通路及自噬通路在足细胞损伤中的最新进展。

Podocytes are terminally differentiated cells located on the outer surface of the glomerular basement membrane with specific architecture and function, and play a key role in maintaining the structure and function of the glomerular filtration barrier. Accumulating evidence suggests that podocytes play a pivotal role in the pathogenesis and progression of glomerular disease and will become an efficient target for the novel therapy of chronic kidney disease. Many studies are now focused on the mechanisms of podocyte injury, the signaling pathways of which provide crucial clues to the pathogenetic mechanism. Interventions on the key factors in the signaling pathways will be potential therapies for podocytopathy. In this review, we highlight both the classic and latest signaling pathways within podocyte injury including Wnt/β-catenin, Notch signaling pathway, podocyte cytoskeleton regulatory signaling pathway, transforming growth factor-β (TGFβ)/ bone morphogenetic protein 7 (BMP-7) signaling pathway, and autophagy pathway.

1
Haraldsson B. A new era of podocyte-targeted therapy for proteinuric kidney disease [J]. N Engl J Med,2013,369(25):2453-2454.
2
Clevers H,Nusse R. Wnt/beta-catenin signaling and disease [J].Cell,2012,149(6):1192-1205.
3
Sharma S,Sirin Y,Susztak K. The story of Notch and chronic kidney disease [J]. Curr Opin Nephrol Hypertens,2011,20(1):56-61.
4
Kato H,Gruenwald A,Suh JH, et al. Wnt/beta-catenin pathway in podocytes integrates cell adhesion,differentiation,and survival[J].J Biol Chem,2011,286(29):26003-26015.
5
Dai C, Stolz DB, Kiss LP, et al. Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria [J]. J Am Soc Nephrol,2009,20(9):1997-2008.
6
Cox SN,Sallustio F,Serino G, et al. Altered modulation of Wntbeta-catenin and PI3K/Akt pathways in IgA nephropathy [J].Kidney Int,2010,78(4):396-407.
7
Heikkila E, Juhila J, Lassila M, et al. beta-Catenin mediates adriamycin-induced albuminuria and podocyte injury in adult mouse kidneys [J]. Nephrol Dial Transplant,2010,25(8):2437-2446.
8
Lin CL,Wang JY,Ko JY,et al. Dickkopf-1 promotes hyperglycemiainduced accumulation of mesangial matrix and renal dysfunction[J]. J Am Soc Nephrol,2010,21(1):124-135.
9
Murea M,Park JK,Sharma S,et al. Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function [J]. Kidney Int,2010,78(5):514-522.
10
Sharma M,Callen S,Zhang D,et al. Activation of Notch signaling pathway in HIV-associated nephropathy [J]. AIDS,2010,24(14):2161-2170.
11
Lasagni L, Ballerini L, Angelotti ML, et al. Notch activation differentially regulates renal progenitors proliferation and differentiation toward the podocyte lineage in glomerular disorders[J]. Stem Cells,2010,28(9):1674-1685.
12
Niranjan T,Bielesz B,Gruenwald A,et al. The Notch pathway in podocytes plays a role in the development of glomerular disease [J].Nat Med,2008,14(3):290-298.
13
Waters AM,Wu MY,Onay T,et al. Ectopic notch activation in developing podocytes causes glomerulosclerosis [J]. J Am Soc Nephrol,2008,19(6):1139-1157.
14
Ahn S H,Susztak K. Getting a notch closer to understanding diabetic kidney disease [J]. Diabetes,2010,59(8):1865-1867.
15
Lin CL,Wang FS,Hsu YC,et al. Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy [J]. Diabete,2010,59(8):1915-1925.
16
Ohse T, Pippin JW, Chang AM, et al. The enigmatic parietal epithelial cell is finally getting noticed: a review [J]. Kidney Int,2009,76(12):1225-1238.
17
Ronconi E, Sagrinati C, Angelotti ML, et al. Regeneration of glomerular podocytes by human renal progenitors [J]. J Am Soc Nephrol,2009,20(2):322-332.
18
Kato H,Susztak K. Repair problems in podocytes:Wnt,Notch,and glomerulosclerosis [J]. Semin Nephrol,2012,32(4):350-356.
19
Scott RP,Hawley SP,Ruston J, et al. Podocyte-specific loss of Cdc42 leads to congenital nephropathy [J]. J Am Soc Nephrol,2012,23(7):1149-1154.
20
Blattner SM,Hodgin JB,Nishio M,et al. Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury [J]. Kidney Int,2013,84(5):920-930.
21
Wang L,Ellis MJ,Gomez JA,et al. Mechanisms of the proteinuria induced by Rho GTPases [J]. Kidney Int, 2012, 81 (11):1075-1085.
22
Zhu L,Jiang R,Aoudjit L,et al. Activation of RhoA in podocytes induces focal segmental glomerulosclerosis [J]. J Am Soc Nephrol,2011,22(9):1621-1630.
23
Jeruschke S,Buscher AK,Oh J,et al. Protective effects of the mTOR inhibitor everolimus on cytoskeletal injury in human podocytes are mediated by RhoA signaling [J]. PLoS One, 2013, 8 (2):e55980.
24
Inoki K,Mori H,Wang J,et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice[J].J Clin Invest,2011,121(6):2181-2196.
25
Gee HY,Saisawat P,Ashraf S,et al. ARHGDIA mutations cause nephrotic syndrome via defective Rho GTPase signaling [J]. J Clin Invest,2013,123(8):3243-3253.
26
Ingelfinger JR. MYO1E,focal segmental glomerulosclerosis, and the cytoskeleton [J]. N Engl J Med,2011,365(4):368-369.
27
Krendel M,Kim SV,Willinger T,et al. Disruption of myosin 1e promotes podocyte injury [J]. J Am Soc Nephrol,2009,20(1):86-94.
28
Chase SE, Encina CV, Stolzenburg LR, et al. Podocyte-specific knockout of myosin 1e disrupts glomerular filtration [J]. Am J Physiol Renal Physiol,2012,303(7): F1099-1106.
29
Bi J,Chase SE,Pellenz CD,et al. Myosin 1e is a component of the glomerular slit diaphragm complex that regulates actin reorganization during cell-cell contact formation in podocytes [J]. Am J Physiol Renal Physiol,2013,305(4): F532-544.
30
Sachs N, Sonnenberg A. Cell-matrix adhesion of podocytes in physiology and disease [J]. Nat Rev Nephrol,2013,9 (4):200-210.
31
Wei C,Moller CC,Altintas MM,et al. Modification of kidney barrier function by the urokinase receptor [J]. Nat Med, 2008, 14(1):55-63.
32
Wei C,El Hindi S,Li J,et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis[J]. Nat Med,2011,17(8):952-960.
33
Maas RJ,Wetzels JF,Deegens JK. Serum-soluble urokinase receptor concentration in primary FSGS [J]. Kidney Int, 2012, 81(10):1043-1044.
34
Parikh SM.Circulating mediators of focal segmental glomerulosclerosis: soluble urokinase plasminogen activator receptor in context [J]. Am J Kidney Dis,2012,59(3):336-339.
35
Jefferson JA,Shankland SJ. Has the circulating permeability factor in primary FSGS been found [J]? Kidney Int, 2013, 84 (2):235-238.
36
Huang J,Liu G,Zhang YM,et al. Plasma soluble urokinase receptor levels are increased but do not distinguish primary from secondary focal segmental glomerulosclerosis [J]. Kidney Int, 2013, 84(2):366-372.
37
Zhang B, Xie S,Shi W,et al. Amiloride off-target effect inhibits podocyte urokinase receptor expression and reduces proteinuria [J].Nephrol Dial Transplant,2012,27(5):1746-1755.
38
Zhang B,Shi W,Ma J,et al. The calcineurin-NFAT pathway allows for urokinase receptor-mediated beta3 integrin signaling to cause podocyte injury [J]. J Mol Med (Berl), 2012, 90 (12):1407-1420.
39
Li R,Zhang L,Shi W,et al. NFAT2 mediates high glucose-induced glomerular podocyte apoptosis through increased Bax expression [J].Exp Cell Res,2013,319(7):992-1000.
40
Zhang L,Li R,Shi W,et al. NFAT2 inhibitor ameliorates diabetic nephropathy and podocyte injury in db/db mice [ J]. Br J Pharmacol,2013,170(2):426-439.
41
Zhu L,Qi XY,Aoudjit L,et al. Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes [J]. Am J Physiol Renal Physiol, 2013, 304 (7):F849-862.
42
Panichi V, Migliori M, Taccola D, et al. Effects of 1,25(OH)2D3 in experimental mesangial proliferative nephritis in rats [J]. Kidney Int,2001,60(1):87-95.
43
Wang Y,Zhou J,Minto AW,et al. Altered vitamin D metabolism in type II diabetic mouse glomeruli may provide protection from diabetic nephropathy [J]. Kidney Int,2006,70(5):882-891.
44
Zhang Z,Sun L,Wang Y,et al. Renoprotective role of the vitamin D receptor in diabetic nephropathy [J]. Kidney Int, 2008, 73(2):163-171.
45
Xiao H,Shi W,Liu S,et al. 1,25-Dihydroxyvitamin D(3) prevents puromycin aminonucleoside-induced apoptosis of glomerular podocytes by activating the phosphatidylinositol 3-kinase/Aktsignaling pathway [J]. Am J Nephrol,2009,30(1):34-43.
46
Xiao HQ,Shi W,Liu SX,et al. Podocyte injury is suppressed by 1,25-dihydroxyvitamin D via modulation of transforming growth factorbeta 1/bone morphogenetic protein-7 signalling in puromycin aminonucleoside nephropathy rats[J]. Clin Exp Pharmacol Physiol,2009,36(7):682-689.
47
Ma J,Zhang B,Liu S,et al. 1,25-dihydroxyvitamin D(3) inhibits podocyte uPAR expression and reduces proteinuria [J]. PLoS One,2013,8(5): e64912.
48
de Zeeuw D,Agarwal R,Amdahl M,et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes ( VITAL study): a randomised controlled trial [J]. Lancet,2010,376(9752):1543-1551.
49
Sonneveld R,Ferre S,Hoenderop JG, et al. Vitamin D downregulates TRPC6 expression in podocyte injury and proteinuric glomerular disease [J]. Am J Pathol,2013,182(4):1196-1204.
50
Tossidou I,Schiffer M. TGF-beta/BMP pathways and the podocyte[J]. Semin Nephrol,2012,32(4):368-376.
51
Jung KY, Chen K, Kretzler M, et al. TGF-beta1 regulates the PINCH-1-integrin-linked kinase-alpha-parvin complex in glomerular cells [J]. J Am Soc Nephrol,2007,18(1):66-73.
52
Niranjan T,Murea M,Susztak K. The pathogenic role of Notch activation in podocytes[J]. Nephron Exp Nephrol,2009,111(4):e73-79.
53
Wang D,Dai C,Li Y,et al. Canonical Wnt/beta-catenin signaling mediates transforming growth factor-beta1-driven podocyte injury and proteinuria [J]. Kidney Int,2011,80(11):1159-1169.
54
Nguyen TQ,Roestenberg P,van Nieuwenhoven FA,et al. CTGF inhibits BMP-7 signaling in diabetic nephropathy [J]. J Am Soc Nephrol,2008,19(11):2098-2107.
55
Mizushima N,Levine B,Cuervo AM,et al. Autophagy fights disease through cellular self-digestion [J]. Nature, 2008, 451(7182):1069-1075.
56
Hartleben B, Godel M, Meyer-Schwesinger C, et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice [J]. J Clin Invest, 2010, 120(4):1084-1096.
57
Narita M,Young AR,Arakawa S,et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes [J]. Science, 2011,332(6032):966-970.
58
Godel M,Hartleben B,Herbach N,et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice [J]. J Clin Invest,2011,121(6):2197-2209.
59
Fang L,Zhou Y,Cao H,et al. Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-induced podocyte injury [J]. PLoS One,2013,8(4): e60546.
60
Letavernier E,Bruneval P,Mandet C,et al. High sirolimus levels may induce focal segmental glomerulosclerosis de novo [J]. Clin J Am Soc Nephrol,2007,2(2):326-333.
61
Munivenkatappa R,Haririan A,Papadimitriou JC,et al. Tubular epithelial cell and podocyte apoptosis with de novo sirolimus based immunosuppression in renal allograft recipients with DGF [J].Histol Histopathol,2010,25(2):189-196.
62
Stylianou K,Petrakis I,Mavroeidi V,et al. Rapamycin induced ultrastructural and molecular alterations in glomerular podocytes in healthy mice [ J]. Nephrol Dial Transplant, 2012, 27 (8):3141-3148.
63
Cina DP,Onay T,Paltoo A,et al. Inhibition of MTOR disrupts autophagic flux in podocytes [J]. J Am Soc Nephrol, 2012, 23(3):412-420.
64
Cina DP,Onay T,Paltoo A,et al. MTOR regulates autophagic flux in the glomerulus [J]. Autophagy,2012,8(4):696-698.
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