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中华肾病研究电子杂志 ›› 2014, Vol. 03 ›› Issue (02) : 99 -103. doi: 10.3877/cma.j.issn.2095-3216.2014.02.008

综述

蛋白尿加速肾小管损伤的作用机制
刘俊1,2, 陈香美1,()   
  1. 1.100853 北京,解放军总医院肾脏病科、解放军肾脏病研究所、肾脏疾病国家重点实验室、国家慢性肾病临床医学研究中心
    2.四川省军区达州军分区医院
  • 出版日期:2014-04-15
  • 通信作者: 陈香美
  • 基金资助:
    国家自然科学青年基金项目(81300598)

Mechanisms of renal tubular injury acceleration by proteinuria

Jun Liu1, Xiangmei Chen1,()   

  1. 1.Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing 100853, China
  • Published:2014-04-15
  • Corresponding author: Xiangmei Chen
引用本文:

刘俊, 陈香美. 蛋白尿加速肾小管损伤的作用机制[J/OL]. 中华肾病研究电子杂志, 2014, 03(02): 99-103.

Jun Liu, Xiangmei Chen. Mechanisms of renal tubular injury acceleration by proteinuria[J/OL]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2014, 03(02): 99-103.

在慢性肾脏病进展过程中最为常见的临床表现是不同程度的蛋白尿。 越来越多的研究表明,持续性蛋白尿与肾小管损伤紧密关联,其在激活肾小管结构损伤和功能障碍中发挥重要的病理生理作用,其机制包括激活内吞受体途径、活化补体、激活肾素血管紧张素系统(RAS)、上调趋化因子和诱导细胞凋亡等作用机理。 本文详细阐述了蛋白尿加速肾小管损伤的作用机制,为临床蛋白尿相关性肾损伤的防治提供重要思路和关键靶点。

Proteinuria of different degrees is the most common clinical manifestation in the progression of chronic kidney disease (CKD). More and more studies showed that persistent proteinuria is closely related to renal tubular injury, as urine protein components can play an important pathophysiological role in the activation of renal tubular structural damage and dysfunction, the mechanism of which includes activation of receptor endocytosis pathway, complement activation, activation of the renin-angiotensin system(RAS), up-regulation of chemokines, and induction of apoptosis, etc. This paper has elaborated on the mechanism of renal tubular injury accelerated by proteinuria, providing important ideas and key targets for prevention and treatment of clinical proteinuria-associated renal injuries.

1
Regeniter A, Freidank H, Dickenmann M, et al. Evaluation of proteinuria and GFR to diagnose and classify kidney disease:systematic review and proof of concept [J]. Eur J Intern Med,2009,20(6):556-561.
2
Comper WD, Hilliard LM, Nikolic-Paterson DJ, et al. Diseasedependent mechanisms of albuminuria [J]. Am J Physiol Renal Physiol,2008,295(6): F1589-F1600.
3
Baines RJ, Brunskill NJ. The molecular interactions between filtered proteins and proximal tubular cells in proteinuria [J]. Nephron Exp Nephrol,2008,110(2): e67-e71.
4
Lee D, Gleich K, Fraser SA, et al. Limited capacity of proximal tubular proteolysis in mice with proteinuria. Am J Physiol Renal Physiol,2013,304(7): F1009-F1019.
5
Theilig F, Kriz W, Jerichow T, et al. Abrogation of protein uptake through megalin-deficient proximal tubules does not safeguard against tubulointerstitial injury [J]. J Am Soc Nephrol, 2007, 18(6):1824-1834.
6
Amsellem S, Gburek J, Hamard G, et al. Cubilin is essential for albumin reabsorption in the renal proximal tubule [J]. J Am Soc Nephrol,2010,21(11):1859-1867.
7
Weyer K, Storm T, Shan J, et al. Mouse model of proximal tubule endocytic dysfunction [J]. Nephrol Dial Transplant, 2011, 26(11):3446-3451.
8
Grösbeck R. Imerslund-Grösbeck syndrome (selective vitamin B12 malabsorption with proteinuria) [J]. Orphanet J Rare Dis, 2006,1:17.
9
Storm T, Emma F, Verroust PJ, et al. A patient with cubilin deficiency [J]. N Engl J Med,2011,364(1):89-91.
10
Yang J, He Y. Expression of renal cubilin and its potential role in tubulointerstitial inflammation induced by albumin overload [J].Front Med China,2008,2(1):25-34.
11
Liu J, Li K, He Y, et al. Anticubilin antisense RNA ameliorates adriamycin- induced tubulointerstitial injury in experimental rats[J]. Am J Med Sci,2011,342(6):494-502.
12
Zou Z, Chung B, Nguyen T, et al. Linking receptor-mediated endocytosis and cell signaling: evidence for regulated intramembrane proteolysis of megalin in proximal tubule [J]. J Biol Chem,2004,279(33):34302-34310.
13
Shah M, Baterina OY Jr, Taupin V, et al. ARH directs megalin to the endocytic recycling compartment to regulate its proteolysis and gene expression [J]. J Cell Biol,2013,202(1):113-127.
14
Diwakar R, Pearson AL, Colville-Nash P, et al. The role played by endocytosis in albumin-induced secretion of TGF-beta1 by proximal tubular epithelial cells[J]. Am J Physiol Renal Physiol,2007,292(5): F1464-F1470.
15
Morita Y, Ikeguchi H, Nakamura J, et al. Complement activation products in the urine from proteinuric patients [J]. J Am Soc Nephrol,2000,11(4):700-707.
16
Gou SJ, Yuan J, Wang C, et al. Alternative complement pathway activation products in urine and kidneys of patients with ANCAassociated GN [J]. Clin J Am Soc Nephrol, 2013, 8 (11):1884-1891.
17
Nangaku M, Pippin J, Couser WG. C6 mediates chronic progression of tubulointerstitial damage in rats with remnant kidneys [J]. J Am Soc Nephrol,2002,13(4):928-936.
18
Abe K, Li K, Sacks SH, et al. The membrane attack complex,C5b-9, up regulates collagen gene expression in renal tubular epithelial cells [J]. Clin Exp Immunol,2004,136(1):60-66.
19
Chen Y, Zhang J, Guo G, et al. Induced B7-H1 expression on human renal tubular epithelial cells by the sublytic terminal complement complex C5b-9 [J]. Mol Immunol, 2009, 46(3):375-383.
20
Sheerin NS, Risley P, Abe K, et al. Synthesis of complement protein C3 in the kidney is an important mediator of local tissue injury [J]. FASEB J,2008,22(4):1065-1072.
21
Tang Z, Lu B, Hatch E, et al. C3a mediates epithelial-tomesenchymal transition in proteinuric nephropathy [J]. J Am Soc Nephrol,2009,20(3):593-603.
22
Peake PW, O'Grady S, Pussell BA, et al. C3a is made by proximal tubular HK-2 cells and activates them via the C3a receptor [J].Kidney Int,1999,56(5):1729-1736.
23
Zoja C, Donadelli R, Colleoni S, et al. Protein overload stimulates RANTES production by proximal tubular cells depending on NFkappa B activation [J]. Kidney Int,1998,53(6):1608-1615.
24
Tang S, Leung JCK, Abe K, et al. Albumin stimulates interleukin-8 expression in proximal tubular epithelial cells in vitro and in vivo[J]. J Clin Invest,2003,111(4):515-527.
25
Dizin E, Hasler U, Nlandu-Khodo S, et al. Albuminuria induces a proinflammatory and profibrotic response in cortical collecting ducts via the 24p3 receptor [J]. Am J Physiol Renal Physiol,2013,305(7): F1053-F1063.
26
Morigi M, Macconi D, Zoja C, et al. Protein overload-induced NFkappa B activation in proximal tubular cells requires H2O2 through a PKC-dependent pathway [J]. J Am Soc Nephrol, 2002, 13(5):1179-1189.
27
Rangan GK, Wang Y, Tay YC, et al. Inhibition of nuclear factorkappa B activation reduces cortical tubulointerstitial injury in proteinuric rats [J]. Kidney Int,1999,56(1):118-134.
28
Takase O, Hirahashi J, Takayanagi A, et al. Gene transfer of truncated IκBα prevents tubulointerstitial injury [J]. Kidney Int,2003,63(2):501-513.
29
Ghosh SS, Massey HD, Krieg R, et al. Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation [J]. Am J Physiol Renal Physiol,2009,296(5): F1146-F1157.
30
Thomas ME, Brunskill NJ, Harris KP, et al. Proteinuria induces tubular cell turnover:a potential mechanism for tubular atrophy[J].Kidney Int,1999,55(3):890-898.
31
Erkan E, De Leon M, Devarajan P. Albumin overload induces apoptosis in LLC-PK1 cells [J]. Am J Physiol Renal Physiol,2001,280(6): F1107-F1114.
32
Morais C, Westhuyzen J, Metharom P, et al. High molecular weight plasma proteins induce apoptosis and Fas/FasL expression in human proximal tubular cells[J]. Nephrol Dial Transplant,2005,20(1):50-58.
33
Erkan E, Devarajan P, Schwartz GJ. Mitochondria are the major targets in albumin-induced apoptosis in proximal tubule cells [J]. J Am Soc Nephrol,2007,18(4):1199-1208.
34
Li X, Pabla N, Wei Q, et al. PKC-delta promotes renal tubular cell apoptosis associated with proteinuria [J]. J Am Soc Nephrol,2010,21(7):1115-1124.
35
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.
36
Wu X, He Y, Jing Y, et al. Albumin overload induces apoptosis in renal tubular epithelial cells through a CHOP-dependent pathway[J]. OMICS,2010,14(1):61-73.
37
Lee EK, Jeong JU, Chang JW, et al. Activation of AMP-activated protein kinase inhibits albumin-induced endoplasmic reticulum stress and apoptosis through inhibition of reactive oxygen species [J].Nephron Exp Nephrol,2012,121(1-2): e38-e48.
38
Shimizu H, Maruyama S, Yuzawa Y, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria [J]. J Am Soc Nephrol,2003,14(6):1496-1505.
39
Viedt C, Dechend R, Fei J, et al. MCP-1 induces inflammatory activation of human tubular epithelial cells: involvement of the transcription factors, nuclear factor-κB and activating protein 21[J]. J Am Soc Nephrol,2002,13(6):1534-1547.
40
Lai KN, Leung JC, Chan LY, et al. Interaction between proximal tubular epithelial cells and infiltrating monocytes/T cells in the proteinuric state [J]. Kidney Int,2007,71(6):526-538.
41
Yazdani S, Poosti F, Kramer AB, et al. Proteinuria triggers renal lymphangiogenesis prior to the development of interstitial fibrosis[J]. PLoS One,2012,7(11): e50209.
42
Matsui T, Yamagishi S, Ueda S, et al. Irbesartan inhibits albuminelicited proximal tubular cell apoptosis and injury in vitro [J].Protein Pept Lett,2010,17(1):74-77.
43
Takao T, Horino T, Kagawa T, et al. Effects of angiotensin Ⅱtype 1 receptor blocker on albumin-induced cell damage in human renal proximal tubular epithelial cells[J]. Am J Nephrol,2009,29(2):102-108.
44
Wolf G, Schroeder R, Ziyadeh FN, et al. Albumin up-regulates the type Ⅱtransforming growth factor-beta receptor in cultured proximal tubular cells [J]. Kidney Int,2004,66(5):1849-1858.
45
Takase O, Marumo T, Imai N, et al. NF-kappaB-dependent increase in intrarenal angiotensin Ⅱinduced by proteinuria [J].Kidney Int,2005,68(2):464-473.
46
Cao W, Zhou QG, Nie J, et al. Albumin overload activates intrarenal renin-angiotensin system through protein kinase C and NADPH oxidase- dependent pathway [J]. J Hypertens, 2011, 29(7):1411-1421.
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