Lack of type VIII collagen in mice ameliorates diabetic nephropathy.
OBJECTIVE
Key features of diabetic nephropathy include the accumulation of extracellular matrix proteins. In recent studies, increased expression of type VIII collagen in the glomeruli and tubulointerstitium of diabetic kidneys has been noted. The objectives of this study were to assess whether type VIII collagen affects the development of diabetic nephropathy and to determine type VIII collagen-dependent pathways in diabetic nephropathy in the mouse model of streptozotocin (STZ)-induced diabetes.


METHODS
Diabetes was induced by STZ injections in collagen VIII-deficient or wild-type mice. Functional and histological analyses were performed 40 days after induction of diabetes. Type VIII collagen expression was assessed by Northern blots, immunohistochemistry, and real-time PCR. Proliferation of primary mesangial cells was measured by thymidine incorporation and direct cell counting. Expression of phosphorylated extracellular signal-regulated kinase (ERK1/2) and p27(Kip1) was assessed by Western blots. Finally, Col8a1 was stably overexpressed in mesangial cells.


RESULTS
Diabetic wild-type mice showed a strong renal induction of type VIII collagen. Diabetic Col8a1(-)/Col8a2(-) animals revealed reduced mesangial expansion and cellularity and extracellular matrix expansion compared with the wild type. These were associated with less albuminuria. High-glucose medium as well as various cytokines induced Col8a1 in cultured mesangial cells. Col8a1(-)/Col8a2(-) mesangial cells revealed decreased proliferation, less phosphorylation of Erk1/2, and increased p27(Kip1) expression. Overexpression of Col8a1 in mesangial cells induced proliferation.


CONCLUSIONS
Lack of type VIII collagen confers renoprotection in diabetic nephropathy. One possible mechanism is that type VIII collagen permits and/or fosters mesangial cell proliferation in early diabetic nephropathy.
Hopfer
Ulrike
U
Department of Medicine, University of Hamburg, Hamburg, Germany. ulrike.hopfer@unibas.ch
Hopfer
Helmut
H
Meyer-Schwesinger
Catherine
C
Loeffler
Ivonne
I
Fukai
Naomi
N
Olsen
Bjorn R
BR
Stahl
Rolf A K
RA
Wolf
Gunter
G
D000818:Animals; D002455:Cell Division; D024102:Collagen Type VIII / Q000172:deficiency* / Q000235:genetics; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005920:Glomerular Mesangium / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics
C507463:Col8a2 protein, mouse; D024102:Collagen Type VIII; D017931:DNA Primers; D012313:RNA