title: Angiotensin II type 1 receptor blockade ameliorates proteinuria in puromycin aminonucleoside nephropathy by inhibiting the reduction of NEPH1 and nephrin.
abstract: BACKGROUND
  The precise pathogenic mechanism and role of angiotensin II (Ang II) action in the development of proteinuria in minimal change nephrotic syndrome (MCNS) is uncertain.
  
  
  METHODS
  The glomerular expressions of the slit diaphragm (SD) molecules nephrin, podocin and NEPH1 in rat puromycin aminonucleoside (PAN) nephropathy, a mimic of MCNS, were analyzed. The effects of Ang II receptor blockade (ARB) (irbesartan 15 mg/kg body weight/day) on proteinuria and on the expression of the SD molecules were analyzed.
  
  
  RESULTS
  mRNA expressions of nephrin, podocin and NEPH1 were decreased to an undetectable level at 1 h. The staining of these SD molecules shifted to a discontinuous pattern, and their intensity was reduced. NEPH1 staining was reduced to an undetectable level on day 10. ARB treatment ameliorated the peak value of proteinuria (237.6 ± 97.0 vs. 359.0 ± 63.3 mg/day, p < 0.05), and prevented the decrease in the mRNA expression of the SD molecules (nephrin 66.96 %, podocin 60.40 %, NEPH1 77.87 % of normal level). The immunofluorescence staining of NEPH1 was restored by ARB. ARB treatment enhanced the expression of NEPH1 of normal rats.
  
  
  CONCLUSIONS
  Dysfunction of the SD molecules including NEPH1 is a crucial initiation event of PAN nephropathy. ARB treatment ameliorates proteinuria in PAN nephropathy by inhibiting the reduction of NEPH1 and nephrin. Ang II action regulates the expression of NEPH1 and nephrin in not only the pathological but also physiological state.
authors.affiliation: Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Fukusumi
authors.affiliation: Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Kayaba
authors.affiliation: Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.
authors.forename: Yukina
authors.initials: Y
authors.lastname: Kitazawa
authors.affiliation: Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tomita
authors.affiliation: Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan. kawachi@med.niigata-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawachi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000077405:Irbesartan; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009402:Nephrosis, Lipoid / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D011692:Puromycin Aminonucleoside; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D047908:Intracellular Signaling Peptides and Proteins; C486607:Kirrel1 protein, rat; D008565:Membrane Proteins; C407223:NPHS2 protein; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C113267:nephrin; D011692:Puromycin Aminonucleoside; D000077405:Irbesartan
keywords: ARB; NEPH1; Nephrin; Podocyte; Slit diaphragm