Takahiro Uchida1, Takashi Oda2, Hanako Takechi3, Hidehito Matsubara3, Atsushi Watanabe3, Kojiro Yamamoto3, Naoki Oshima3, Yutaka Sakurai4, Takako Kono5, Hideyuki Shimazaki5, Seiichi Tamai5, Hiroo Kumagai3. 1. Department of Nephrology and Endocrinology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan. dri1905@ndmc.ac.jp. 2. Department of Nephrology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan. 3. Department of Nephrology and Endocrinology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan. 4. Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan. 5. Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.
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.
BACKGROUND:Plasmin has recently been reported to be associated with renal fibrosis in experimental models, but its role in humanrenal 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.
Entities:
Keywords:
Epithelial-to-mesenchymal transition; Fibrosis; IgA nephropathy; Plasmin
Authors: Ian S D Roberts; H Terence Cook; Stéphan Troyanov; Charles E Alpers; Alessandro Amore; Jonathan Barratt; Francois Berthoux; Stephen Bonsib; Jan A Bruijn; Daniel C Cattran; Rosanna Coppo; Vivette D'Agati; Giuseppe D'Amico; Steven Emancipator; Francesco Emma; John Feehally; Franco Ferrario; Fernando C Fervenza; Sandrine Florquin; Agnes Fogo; Colin C Geddes; Hermann-Josef Groene; Mark Haas; Andrew M Herzenberg; Prue A Hill; Ronald J Hogg; Stephen I Hsu; J Charles Jennette; Kensuke Joh; Bruce A Julian; Tetsuya Kawamura; Fernand M Lai; Lei-Shi Li; Philip K T Li; Zhi-Hong Liu; Bruce Mackinnon; Sergio Mezzano; F Paolo Schena; Yasuhiko Tomino; Patrick D Walker; Haiyan Wang; Jan J Weening; Nori Yoshikawa; Hong Zhang Journal: Kidney Int Date: 2009-07-01 Impact factor: 10.612
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