UUO

apoptotic cell

ECM

cellular infiltration

myofibroblast accumulation

EMT

infiltratio

n

prolife

ratio

n

macrophagemyofibroblast

epithelial cell

ECM

tubular atrophy

+-

growth factors/cytokines Collagen production

pro

lifer

atio

n

apoptos

isfibroblast

Fig 1, Bascands & Schanstra

CD44

circulatio

n

interstitium

CCR1

chemokines osteopontin

L-selectin

sulfatide

endothelial cells

Fig 2, Bascands & Schanstra

Interstitial fibroblast

tubule

matrix accumulation

myofibroblast

TGF

Bone marrow derived cells

Epithelial Mesenchymal Transition

1) Loss of epithelial adhesion properties2) SMA expression and actin reorganization3) Disruption of the tubular basement membrane4) Enhances epithelial cell migration and invasion

interstitium

activation

fibroblast

tPA knockout

MMP9 expression

Fig 3, Bascands & Schanstra

AII

angiotensinogen

AI

renin

ACE

bradykinin

kininogen

kallikrein

inactive peptides

AT1 receptor

B2 receptor

TGF

PAI-1

matrix

PA

plasminogen plasmin

ACE-inhibitors

MMPpro-MMP

matrix

cellular infiltration

HGF

EMTMMP-9

Fig 4, Bascands & Schanstra

Nucleus

TNFAII

AT1AT2 TNFR1

TNFR2

angiotensinogenAI

NF-BIB

NF-B

IBP

IB degradation NF-B

NF-B motif

gene transcription

TNFangiotensinogen

IB kinases

renin

ACE

postive regulation loops

proinflammatory and profibrotic cytokines

inflammationmatrix expression

fibrosis

Fig 5, Bascands & Schanstra

Nucleus

enhancer of TGF regulated genes

gene transcription

R-II

R-ITGF

TG

F

R-IR-II

TG

F

R-I

R-II

P

SMAD2/3 P

SMAD2/3

SMAD4

SMAD2/3

P

SMAD4

EMTcellular infiltration apoptosis

RhoA/Rock stress fiber formationp38MAPKs reorganization of actin cytoskeleton

Tubulointerstitial fibrosis

latent-TGF

plasminintegrin V6

decorin

Fig 6, Bascands & Schanstra