The renal expression of transforming growth factor-beta isoforms and theirreceptors in acute and chronic experimental diabetes in rats

Transforming growth factors-beta (TGF-beta) are fibrogenic factors that hav e been strongly implicated in the development of diabetic nephropathy. Our aim was to use two animal models [the streptozotocin (STZ)-induced diabetic rat and the genetically prone biobreeding (BB) rat] to fully characterize the responses of the renal TGF-beta system in both short- and long-term dia betes. In this study changes in the entire renal TGF-beta system, at both p rotein and messenger RNA (mRNA) levels, have been characterized using the t echniques of immunocytochemistry, Western blotting, and ribonuclease protec tion assay. We also used Western blotting of pro-collagen-I C-peptide to de monstrate that the rate of fibrogenesis was highest over the first 2 weeks of diabetes. TGF-beta 1, TGF-beta 2, and receptor mRNA and protein were det ected in the control nondiabetic kidney. It was found that dramatic and dyn amic changes occur in all parts of the renal TGF-beta axis in both models o f experimental diabetes, but TGF-beta 2 and TGF-beta RII proteins were the predominant responsive element, particularly during the acute phase of dise ase. For example, during the acute phase of disease (0-30 days), although r enal TGF-beta 1 mRNA levels were elevated, no increases in the correspondin g protein were detected in the kidney. By contrast, in the absence of chang es in TGF-beta 2 mRNA levels, twice as much TGF-beta 2 protein was measured in the kidney by day 30 of STZ-induced diabetes compared with day 0 contro ls analyzed by Western blotting (P < 0.05), and the protein was localized b oth to the nuclei and cytoplasm of glomerular cells, analyzed by immunocyto chemistry. In addition, three times as much TGF-beta RII protein was found by day 90 of STZ-induced diabetes compared with day 0 controls, making this the most responsive receptor type. These results suggest that the entire T GF-beta axis has a role in the etiology of kidney fibrosis and could be man ipulated therapeutically to preserve kidney function.