Collagen VIII influences epithelial phenotypic changes in experimental diabetic nephropathy

Loeffler I, Liebisch M, Wolf G. Collagen VIII influences epithelial phenotypic changes in experimental diabetic nephropathy. Am J Physiol Renal Physiol 303: F733-F745, 2012. First published July 3, 2012; doi: 10.1152/ajprenal.00212.2012.-Epithelial-to-mesenchymal transition (EMT) is an important mechanism of renal tubulo-interstitial fibrosis in diabetic nephropathy (DN). Inducers of EMT, among others, are transforming growth factor-beta(1) (TGF-beta(1)) as well as extracellular collagens. In renal cells of diabetic mice and in kidneys of patients with DN, the expression of collagen VIII (gene: Col8 alpha 1/alpha 2) is enhanced and characteristic features of DN in streptozotocin (STZ)-induced diabetic Col8 alpha 1/alpha 2 knockout-(KO) mice are attenuated compared with diabetic wild-type mice. This study aimed to investigate whether collagen type VIII may influence the induction of EMT. DN was induced in wild-type and Col8 alpha 1/alpha 2-KO mice using the established and widely accepted low-dose STZ model [treatment for 5 consecutive days (50 mg/kg)]. Healthy and diabetic mice were analyzed for changes in renal function and the expression of EMT-related genes and proteins. Renal morphology, fibrosis, and various EMT markers were studied in kidneys using immunohistological and molecular biological methods. Knockout of Col8 alpha 1/alpha 2 attenuated albuminuria, extracellular matrix production, as well as fibrosis. Furthermore, the kidneys of diabetic Col8 alpha 1/alpha 2-KO mice showed a marked reduction in interstitial myofibroblasts, and in tubular cells the inhibition of the expression of epithelial markers as well as the expression of typical mesenchymal markers was reduced. The present study demonstrates that in contrast to diabetic wild-type mice EMT-like changes were attenuated in diabetic Col8 alpha 1/alpha 2-KO mice, which indicates that either collagen VIII may be one of the major inducers of EMT-like changes in kidneys of diabetic wild-type mice or/possibly the lack of Col8 alpha 1/alpha 2 disrupts TGF-beta 1-induced EMT-like changes.