title: 1,25-dihydroxyvitamin D(3) inhibits podocyte uPAR expression and reduces proteinuria.
abstract: BACKGROUND
  Accumulating studies have demonstrated that 1,25-Dihydroxyvitamin D(3) (1,25(OH)2D3) reduces proteinuria and protects podocytes from injury. Recently, urokinase receptor (uPAR) and its soluble form have been shown to cause podocyte injury and focal segmental glomerulosclerosis (FSGS). Here, our findings showed that 1,25(OH)2D3 did inhibit podocyte uPAR expression and attenuate proteinuria and podocyte injury.
  
  
  RESULTS
  In this study, the antiproteinuric effect of 1,25(OH)2D3 was examined in the lipopolysaccharide mice model of transient proteinuria (LPS mice) and in the 5/6 nephrectomy rat FSGS model(NTX rats). uPAR protein expression were tested by flow cytometry, immune cytochemistry and western blot analysis, and uPAR mRNA expression by real-time quantitative PCR in cultured podocytes and kidney glomeruli isolated from mice and rats. Podocyte motility was observed by transwell migration assay and wound healing assay. Podocyte foot processes effacement was identified by transmission electron microscopy. We found that 1,25(OH)2D3 inhibited podocyte uPAR mRNA and protein synthesis in LPS-treated podocytes, LPS mice and NTX rats, along with 1,25(OH)2D3 reducing proteinuria in NTX rats and LPS mice.1,25(OH)2D3 reduced glomerulosclerosis in NTX rats and alleviated podocyte foot processes effacement in LPS mice. Transwell migration assay and wound healing assay showed that LPS-induced podocyte motility, irrespective of random or directed motility, were substantially reduced by 1,25(OH)2D3.
  
  
  CONCLUSIONS
  Our results demonstrated that 1,25(OH)2D3 inhibited podocyte uPAR expression in vitro and in vivo, which may be an unanticipated off target effect of 1,25(OH)2D3 and explain its antiproteinuric effect in the 5/6 nephrectomy rat FSGS model and the LPS mouse model of transient proteinuria.
authors.affiliation: Southern Medical University, Guangzhou, China.
authors.forename: Jianchao
authors.initials: J
authors.lastname: Ma
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Shuangxin
authors.initials: S
authors.lastname: Liu
authors.forename: Shaoting
authors.initials: S
authors.lastname: Xie
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.forename: Juan
authors.initials: J
authors.lastname: Ma
authors.forename: Yujun
authors.initials: Y
authors.lastname: Deng
authors.forename: Wenjian
authors.initials: W
authors.lastname: Wang
authors.forename: Lixia
authors.initials: L
authors.lastname: Xu
authors.forename: Ruizhao
authors.initials: R
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Chunping
authors.initials: C
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D011507:Proteinuria / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D014807:Vitamin D / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D