Renal tubulointerstitial fibrosis in OVE26 type 1 diabetic mice.
OBJECTIVE
Tubulointerstitial fibrosis (TIF) is a prominent feature of progressive diabetic nephropathy. The goal of this study was to determine if hallmarks of TIF occur in the transgenic OVE26 type 1 diabetic mouse and define signaling events associated with TIF.


METHODS
The expression patterns of several phenotypic markers of TIF were determined in kidneys of OVE26 diabetic and control mice by immunohistochemistry and immunoblot analysis.


RESULTS
Pathological signatures of TIF are an accumulation of myofibroblasts and excessive deposition of extracellular matrix in the tubulointerstitium. Kidneys from OVE26 diabetic animals exhibited an increase in tubulointerstitial myofibroblast marker (alpha-smooth muscle actin), fibronectin and collagen I staining. Abundance of the pro-fibrotic cytokine TGF-beta was also enhanced in diabetic tubules. As injury involving loss of epithelial cell-cell contact promotes tissue fibrosis, we examined expression of the adhesion protein, E-cadherin. The percent of E-cadherin-stained tubules was decreased in diabetic kidneys. Prominent regulators of TGF-beta signaling, glycogen synthase kinase-3 (GSK-3) alpha and beta, were also differentially expressed.


CONCLUSIONS
These results indicate that TGF-beta-induced TIF occurs in OVE26 diabetic mice, providing a practical in vivo model for defining novel regulatory events and treatment strategies for diabetes-induced TIF.
Powell
David W
DW
Department of Medicine, University of Louisville School of Medicine, Louisville, Ky., USA. david.powell@louisville.edu
Bertram
Clinton C
CC
Cummins
Timothy D
TD
Barati
Michelle T
MT
Zheng
Shirong
S
Epstein
Paul N
PN
Klein
Jon B
JB
D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009395:Nephritis, Interstitial / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000199:Actins; D015820:Cadherins; D016212:Transforming Growth Factor beta; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3