1. - + 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

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

3. 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

4. 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

5. 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

6. 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