Lack of Type VIII Collagen in Mice Ameliorates Diabetic Nephropathy

Abstract

Objective - Key features of diabetic nephropathy (DN) include the accumulation of extracellular matrix proteins. Recent studies noted an increased expression of type VIII collagen in glomeruli and the tubulointerstitium of diabetic kidneys. The objectives of this study were to assess whether type VIII collagen affects the development of DN and to determine type VIII collagen dependent pathways in DN in the mouse model of streptozotocin induced diabetes.

Research Design and Methods - Diabetes was induced by streptozotocin injections in collagen VIII deficient or wildtype 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 Erk 1, 2 kinase and p27^Kip1 was assessed by Western blots. Finally, Col8a1 was stably overexpressed in mesangial cells.

Results - Diabetic wildtype mice showed a strong renal induction of type VIII collagen. Diabetic Col8a1^--/Col8a2^-- animals revealed a reduced mesangial expansion, cellularity and extracellular matrix expansion compared to the wildtype. This was associated with less albuminuria. High glucose medium as well as various cytokines induced Col8a1 in cultured mesangial cells. Col8a1^--/Col8a2^-- mesangial cells revealed a decreased proliferation, less phosphorylation of Erk 1,2 and increased p27^Kip1 expression. Overexpression of Col8a1 in mesangial cells induced proliferation.

Conclusions - Lack of type VIII collagen confers renoprotection in DN. One mechanism might be that type VIII collagen permits and / or fosters mesangial cell proliferation in early DN.