- + cellular infiltration myofibroblast accumulation tubular atrophy Fig 1, Bascands & Schanstra cellular infiltration myofibroblast accumulation tubular atrophy ECM infiltration UUO EMT apoptosis proliferation proliferation - + ECM fibroblast growth factors/cytokines Collagen production epithelial cell macrophage apoptotic cell myofibroblast

circulation interstitium endothelial cells Fig 2, Bascands & Schanstra CCR1 CD44 circulation endothelial cells L-selectin chemokines osteopontin sulfatide interstitium

TGF Interstitial fibroblast activation Fig 3, Bascands & Schanstra TGF Interstitial fibroblast activation Epithelial Mesenchymal Transition 1) Loss of epithelial adhesion properties 2) a-SMA expression and actin reorganization 3) Disruption of the tubular basement membrane 4) Enhances epithelial cell migration and invasion tubule fibroblast myofibroblast MMP9 expression Bone marrow derived cells matrix accumulation tPA knockout interstitium

cellular infiltration Fig 4, Bascands & Schanstra angiotensinogen kininogen renin kallikrein ACE-inhibitors AI matrix bradykinin TGF AII ACE inactive peptides AT1 receptor PAI-1 cellular infiltration PA HGF plasminogen plasmin B2 receptor pro-MMP MMP matrix MMP-9 EMT

angiotensinogen AI AII TNFa AT1 AT2 TNFR1 TNFR2 IB kinases NF-B IB Fig 5, Bascands & Schanstra angiotensinogen AI renin ACE AII TNFa postive regulation loops AT1 AT2 TNFR1 TNFR2 IB kinases NF-B IB NF-B IB P TNFa angiotensinogen gene transcription NF-B IkB degradation proinflammatory and profibrotic cytokines inflammation matrix expression NF-kB motif Nucleus fibrosis

Tubulointerstitial fibrosis Fig 6, Bascands & Schanstra decorin TGF R-I R-II TGF R-I R-II TGF R-I P SMAD2/3 R-II RhoA/Rock stress fiber formation p38MAPKs reorganization of actin cytoskeleton SMAD2/3 P plasmin integrin aVb6 SMAD4 Nucleus gene transcription EMT cellular infiltration apoptosis SMAD2/3 P SMAD4 enhancer of TGFb regulated genes latent-TGF Tubulointerstitial fibrosis