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Nox‐2 Is a Modulator of Fibrogenesis in Kidney Allografts
Author(s) -
Djamali A.,
Vidyasagar A.,
Adulla M.,
Hullett D.,
Reese S.
Publication year - 2009
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2008.02463.x
Subject(s) - apocynin , nox1 , nadph oxidase , medicine , fibrosis , downregulation and upregulation , myofibroblast , nox , cancer research , oxidative stress , microbiology and biotechnology , pathology , biology , chemistry , biochemistry , organic chemistry , combustion , gene
We studied the role of classical phagocytic NADPH oxidase (Nox) in the pathogenesis of kidney allograft tubulointerstitial fibrosis. Immunofluorescence studies showed that Nox‐2 and p22phox (electron transfer subunits of Nox) colocalized in the tubulointerstitium of human kidney allografts. Tubular Nox‐2 also colocalized with α‐SMA in areas of injury, suggestive of epithelial‐to‐mesenchymal transition (EMT). Interstitial macrophages (CD68 + ) and myofibroblasts (α‐SMA + ) expressed Nox‐2 while graft infiltrating T cells (CD3 + ) and mature fibroblasts (S100A4 + ) were Nox‐2 − . These results were confirmed in the Fisher‐to‐Lewis rat kidney transplant model. Areas of tubulitis were associated with Nox‐2 and α‐SMA, suggestive of EMT. Immunoblot analyses showed that Nox‐2 upregulation was associated with oxidative stress (nitrotyrosine) and fibrogenesis (α‐SMA and phospho‐Smad2) at 3 weeks and 6 months. Allografts treated with Nox inhibitors (DPI or apocynin) for 1 week showed reduced fibronectin and phospho‐Smad2 and increased E‐cadherin levels. Cyclosporine A, TGF‐β1 and angiotensin II increased Nox‐2 mRNA levels 2‐ to 7‐fold in vitro (NRK52E cells). Treatment with specific Nox inhibitors (DPI or apocynin) prevented the downregulation of E‐cadherin and upregulation of fibronectin transcripts. In aggregate, these studies suggest that Nox‐2 is involved in the pathogenesis of allograft tubulointerstitial fibrosis via activation transcription factor Smad2, EMT and myofibroblasts.