title: Podocyte-specific NF-κB inhibition ameliorates proteinuria in adriamycin-induced nephropathy in mice.
abstract: BACKGROUND
  Podocytes play a central role in the formation of the glomerular filtration barrier in the kidney, and their dysfunction has been shown to result in proteinuria. In the present study, we sought to determine the cell-autonomous role of NF-κB, a proinflammatory signaling, within podocytes in proteinuric kidney disease.
  
  
  METHODS
  Podocyte-specific IκBΔN transgenic (Pod-IκBΔN) mice, in which NF-κB was inhibited specifically in podocytes, were generated by the Cre-loxP technology, and their phenotype was compared with control mice in adriamycin-induced nephropathy.
  
  
  RESULTS
  Pod-IκBΔN mice were phenotypically normal and did not exhibit proteinuria at the physiological condition. By the intravenous administration of adriamycin, overt proteinuria appeared in Pod-IκBΔN mice, as well as in control mice. However, of interest, the amount of proteinuria was significantly lower in adriamycin-injected Pod-IκBΔN mice (373 ± 122 mg albumin/g creatinine), compared with adriamycin-injected control mice (992 ± 395 mg albumin/g creatinine). Expression of podocyte-selective slit diaphragm-associated proteins, such as nephrin and synaptopodin, was markedly decreased by adriamycin injection in control mice, whereas the reduction was attenuated in Pod-IκBΔN mice. Adriamycin-induced reduction in synaptopodin expression was also seen in cultured podocytes derived from control mice, but not in those from Pod-IκBΔN mice.
  
  
  CONCLUSIONS
  Because nephrin and synaptopodin are essential for the maintenance of the slit diaphragm in podocytes, these results suggest that proteinuria in adriamycin-induced nephropathy is caused by the reduction in expression of these proteins. The results also suggest that the NF-κB signalling in podocytes cell-autonomously contributes to proteinuria through the regulation of these proteins.
authors.affiliation: Apheresis and Dialysis Center, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Apheresis and Dialysis Center, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan. tayoshida-npr@umin.ac.jp.|Department of General Medicine, School of Medicine, Keio University, Tokyo, 160-8582, Japan. tayoshida-npr@umin.ac.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Emergency and Critical Care Medicine, School of Medicine, Keio University, Tokyo, 160-8582, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Emergency and Critical Care Medicine, School of Medicine, Keio University, Tokyo, 160-8582, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Homma
authors.affiliation: Apheresis and Dialysis Center, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan.|Department of General Medicine, School of Medicine, Keio University, Tokyo, 160-8582, Japan.
authors.forename: Matsuhiko
authors.initials: M
authors.lastname: Hayashi
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004317:Doxorubicin; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D020672:I-kappa B Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D016328:NF-kappa B; C503968:Synpo protein, mouse; C113267:nephrin; D004317:Doxorubicin; C045073:Cre recombinase; D019426:Integrases
keywords: Albuminuria; Kidney; NF-κB; Podocyte