title: Role of tubulointerstitial plasmin in the progression of IgA nephropathy.
abstract: BACKGROUND
  Plasmin has recently been reported to be associated with renal fibrosis in experimental models, but its role in human renal diseases is unclear.
  
  
  METHODS
  Fifty-seven patients with IgA nephropathy (IgAN) were evaluated retrospectively. Plasmin in their renal biopsy tissues was assessed by in situ zymography using a plasmin-sensitive synthetic peptide, and the relationships between patients' histologic or clinical parameters and their renal plasmin activity [assessed semiquantitatively by calculating the positively stained percentage of the total tubulointerstitial (TI) area] were evaluated.
  
  
  RESULTS
  Plasmin activity was observed almost exclusively in the TI space (mainly in the interstitium and partly in the tubular epithelial cells) and was significantly stronger in patients with TI lesion (tubular atrophy/interstitial fibrosis and tubulointerstitial inflammation) than in those without TI lesion. It was significantly and positively correlated with the global glomerulosclerosis rate and significantly and negatively correlated with estimated glomerular filtration rate not only at the time of renal biopsy but also at the end of the follow-up period. Double stainings for plasmin activity and inflammatory cells, cytokeratin, or α-smooth muscle actin (α-SMA) in selected patients revealed TI infiltration of inflammatory cells, attenuated tubular epithelial expression of cytokeratin, and augmented interstitial expression of α-SMA close to upregulated plasmin activity in the TI space.
  
  
  CONCLUSIONS
  These data suggest that TI plasmin is associated with TI inflammation leading to renal fibrosis, and can cause the decline in renal function seen in patients with IgAN. Reducing plasmin in situ may therefore be a promising therapeutic approach slowing renal fibrogenesis and improving renal function.
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan. dri1905@ndmc.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Nephrology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Oda
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
authors.forename: Hanako
authors.initials: H
authors.lastname: Takechi
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Matsubara
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Oshima
authors.affiliation: Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Kono
authors.affiliation: Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shimazaki
authors.affiliation: Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Tamai
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Kumagai
mesh_terms: D000199:Actins / Q000032:analysis; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D018450:Disease Progression; D004847:Epithelial Cells / Q000737:chemistry* / Q000473:pathology; D005260:Female; D005341:Fibrinolysin / Q000032:analysis*; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007633:Keratins / Q000032:analysis; D007684:Kidney Tubules / Q000737:chemistry* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D015415:Biomarkers; D007633:Keratins; D005341:Fibrinolysin
keywords: Epithelial-to-mesenchymal transition; Fibrosis; IgA nephropathy; Plasmin