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The Renal Expression of Transforming Growth Factor-ß Isoforms and Their Receptors in Acute and Chronic Experimental Diabetes in Rats¹

Department of Medicine (C.H., H.G., M.C.S., A.L.), University of Birmingham, Birmingham, B15 2TH, United Kingdom; Institute of Experimental Clinical Research (A.F.), Aarhus Kommunehospital, DK-8000 Aarhus C, Denmark; Lawson Research Institute (J.P., D.J.H.), St. Joseph’s Health Centre, University of Western Ontario, London, Ontario, Canada; and Department of Medicine (C.R.T.), St. Thomas’s Hospital, London, SE1 7EH, United Kingdom

Address all correspondence and requests for reprints to: Dr. A. Logan, Department of Medicine, University of Birmingham, Wolfson Research Laboratories, Queen Elizabeth Medical Centre, Edgbaston, Birmingham, B15 2TH. E-mail: a.logan{at}bham.ac.uk

Transforming growth factors-ß (TGF-ß) are fibrogenic factors that have 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-ß system in both short- and long-term diabetes. In this study changes in the entire renal TGF-ß system, at both protein and messenger RNA (mRNA) levels, have been characterized using the techniques of immunocytochemistry, Western blotting, and ribonuclease protection assay. We also used Western blotting of pro-collagen-I C-peptide to demonstrate that the rate of fibrogenesis was highest over the first 2 weeks of diabetes. TGF-ß1, TGF-ß2, and receptor mRNA and protein were detected in the control nondiabetic kidney. It was found that dramatic and dynamic changes occur in all parts of the renal TGF-ß axis in both models of experimental diabetes, but TGF-ß2 and TGF-ßRII proteins were the predominant responsive element, particularly during the acute phase of disease. For example, during the acute phase of disease (0–30 days), although renal TGF-ß1 mRNA levels were elevated, no increases in the corresponding protein were detected in the kidney. By contrast, in the absence of changes in TGF-ß2 mRNA levels, twice as much TGF-ß2 protein was measured in the kidney by day 30 of STZ-induced diabetes compared with day 0 controls analyzed by Western blotting (P < 0.05), and the protein was localized both to the nuclei and cytoplasm of glomerular cells, analyzed by immunocytochemistry. In addition, three times as much TGF-ßRII 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 TGF-ß axis has a role in the etiology of kidney fibrosis and could be manipulated therapeutically to preserve kidney function.