title: Multi-glycoside of Tripterygium wilfordii Hook. f. reduces proteinuria through improving podocyte slit diaphragm dysfunction in anti-Thy1.1 glomerulonephritis.
abstract: BACKGROUND
  Multi-glycoside of Tripterygium wilfordii Hook. f. (GTW) has been proved clinically effective in reducing proteinuria in chronic kidney disease in China. However, the mechanisms involved are still unclear. In this study we examined the effects of GTW at the different dosages on proteinuria and podocyte slit diaphragm (SD) dysfunction in anti-Thy1.1 glomerulonephritis (GN).
  
  
  METHODS
  Rats with anti-Thy1.1 GN were divided into 2 groups, a GTW group and a vehicle group, and sacrificed at 30 min, on day 7, and on day 14 in Experiments 1, 2 and 3, respectively. The administration of GTW at the moderate and high doses was started 3 days before or at the same time of antibody injection till sacrifice. Proteinuria was determined in Experiments 1, 2, and 3. After sacrifice, the staining intensity of SD-associated key functional molecules including nephrin and podocin, podocyte structure, mesangial change, macrophage infiltration, and blood biochemical parameters were examined, respectively. Protein and mRNA expressions of nephrin and podocin in glomeruli were also investigated. Besides, liver histological characteristics were analyzed.
  
  
  RESULTS
  In Experiment 1, GTW pretreatment at the medium dose (75 mg/kg body weight) caused no influence on the induction of anti-Thy1.1 GN and the basal nephrin expression. In Experiment 2, the high dosage (100mg/kg body weight) of GTW ameliorated proteinuria, the distribution of nephrin and podocin, mesangial proliferation, and the activated macrophage accumulation, as compared with vehicle group (P<0.05). Additionally, it increased mRNA and protein expressions of nephrin and podocin in glomeruli on day 7, but had no influence on podocyte structure. In Experiment 3, the medium dosage (75 mg/kg body weight) of GTW improved proteinuria, the partial matrix expansion, and the distribution of nephrin and podocin on day 14, as compared with anti-Thy1.1 GN rats (P<0.05). GTW at the high or moderate dose did not affect hepatic function on day 7 and on day 14.
  
  
  CONCLUSIONS
  Podocyte SD dysfunction, such as the disordered distribution and down-regulation of nephrin and podocin expression, is critically involved in the pathogenesis of anti-Thy1.1 GN induced by mAb 1-22-3. The restoration of the distribution and expression of nephrin and podocin by GTW could be an important mechanism by which GTW ameliorates proteinuria and podocyte SD dysfunction.
authors.affiliation: Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
authors.forename: Yi-Gang
authors.initials: YG
authors.lastname: Wan
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Zhen
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Che
authors.forename: Hong-Ping
authors.initials: HP
authors.lastname: Pu
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Ruan
authors.forename: Qiao-Jing
authors.initials: QJ
authors.lastname: Yan
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D050199:Podocytes / Q000276:immunology / Q000378:metabolism*; D011507:Proteinuria / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018800:Thy-1 Antigens; D029757:Tripterygium
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D010936:Plant Extracts; D012333:RNA, Messenger; D018800:Thy-1 Antigens; C113267:nephrin