Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells.

We recently showed in a tetracycline-controlled transgenic mouse model that overexpression of transforming growth factor (TGF)-beta1 in renal tubules induces widespread peritubular fibrosis and focal degeneration of nephrons. In the present study we have analyzed the mechanisms underlying these phenomena. The initial response to tubular cell-derived TGF-beta1 consisted of a robust proliferation of peritubular cells and deposition of collagen. On sustained expression, nephrons degenerated in a focal pattern. This process started with tubular dedifferentiation and proceeded to total decomposition of tubular cells by autophagy. The final outcome was empty collapsed remnants of tubular basement membrane embedded into a dense collagenous fibrous tissue. The corresponding glomeruli survived as atubular remnants. Thus, TGF-beta1 driven autophagy may represent a novel mechanism of tubular decomposition. The fibrosis seen in between intact tubules and in areas of tubular decomposition resulted from myofibroblasts that were derived from local fibroblasts. No evidence was found for a transition of tubular cells into myofibroblasts. Neither tracing of injured tubules in electron micrographs nor genetic tagging of tubular epithelial cells revealed cells transgressing the tubular basement membrane. In conclusion, overexpression of TGF-beta1 in renal tubules in vivo induces interstitial proliferation, tubular autophagy, and fibrosis, but not epithelial-to-mesenchymal transition.

New insights into structural patterns encountered in glomerulosclerosis.

PURPOSE OF REVIEW: The term 'focal segmental glomerulosclerosis' covers a variety of diseases with different histopathological patterns. There is a need for clues to interpret histological findings in terms of etiology. Studies in transgenic animal models published in recent years have targeted the podocyte with respect to its impact on the development of glomerulosclerosis. Our aim was to survey those models in an attempt to discover correlations between histopathological patterns and pathogenic mechanisms. RECENT FINDINGS: The most obvious conclusion to draw from recent studies is that virtually all forms of glomerulosclerosis start with a lesion or dysfunction of podocytes. In hereditary glomerular diseases and transgenic animal models, two patterns of glomerular degeneration may be distinguished. All diseases with late onset appear to follow the 'classic' pathway to focal segmental glomerulosclerosis, starting with an adhesion of the tuft to the Bowman's capsule and eventually leading to nephron degeneration. In contrast, those with early onset frequently exhibit changes that indicate a severe dysregulation of podocyte function resulting in diffuse global endocapillary damage (i.e. mesangial expansion and rarefaction of capillaries). SUMMARY: Such insights derived from animal models might be useful in elucidating the mechanisms of multifactorial human diseases like diabetic glomerulopathy.