The Protective Role of Smad7 in Diabetic Kidney Disease: Mechanism and Therapeutic Potential

OBJECTIVE - Although Smad3 has been considered as a downstream mediator of transforming growth factor-β (TGF-β) signaling in diabetes complications, the role of Smad7 in diabetes remains largely unclear. The current study tests the hypothesis that Smad7 may play a protective role and has therapeutic potential for diabetic kidney disease. RESEARCH DESIGN AND METHODS - Protective role of Smad7 in diabetic kidney disease was examined in streptozotocin-induced diabetic mice that have Smad7 gene knockout (KO) and in diabetic rats given Smad7 gene transfer using an ultrasound-microbubble-mediated technique. RESULTS - We found that mice deficient for Smad7 developed more severe diabetic kidney injury than wild-type mice as evidenced by a significant increase in microalbuminuria, renal fibrosis (collagen I, IV, and fibronectin), and renal inflammation (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α], monocyte chemoattractant protein-1 [MCP-1], intracellular adhesion molecule-1 [ICAM-1], and macrophages). Further studies revealed that enhanced renal fibrosis and inflammation in Smad7 KO mice with diabetes were associated with increased activation of both TGF-β/Smad2/3 and nuclear factor-κB (NF-κB) signaling pathways. To develop a therapeutic potential for diabetic kidney disease, Smad7 gene was transferred into the kidney in diabetic rats by an ultrasound-microbubble-mediated technique. Although overexpression of renal Smad7 had no effect on levels of blood glucose, it significantly attenuated the development of microalbuminuria, TGF-β/Smad3-mediated renal fibrosis such as collagen I and IV and fibronectin accumulation and NF-κB/p65-driven renal inflammation including IL-1β, TNF-α, MCP-1, and ICAM-1 expression and macrophage infiltration in diabetic rats. CONCLUSIONS-Smad7 plays a protective role in diabetic renal injury. Overexpression of Smad7 may represent a novel therapy for the diabetic kidney complication. © 2011 by the American Diabetes Association.link_to_subscribed_fulltex

Japan-Australian co-operative program on research and development of technology for the management of high level radioactive wastes, 1985 to 1998: final report.

The first five year phase (Phase I) of this Co-operative program commenced in 1985 as a consequence of technical and diplomatic discussions is the early 1980's. During Phase I, effective mechanisms of information transfer were established through personnel exchanges between JAERI and ANSTO, and a number of technical workshops. At the end of Phase I it was agreed that the Program should be extended into a second five-year period from 1990 to 1995, designated as Phase II. This latter phase was subsequently extended for a further three-year period from 1995 to 1998 to allow the collection of additional information on long-term accelerated damage tests and preparation of a final report. At the end of each phase of the Co-operative Program details results have been published in jointly-authored, formal documents. The key results, significance and recommendations of the entire Co-operative Program are summarised herein. The Co-operative Program has enhanced the excellent co-operative working relationship between the two institutions, and the arrangements developed under the original agreement should serve as a model for any other co-operative projects developed in the future. The main activities in the first phase of the Co-operative Program were the preparation, characterisation and subsequent testing of curium-doped Synroc containing simulated waste of the type produced by the PNC reprocessing facility at Tokyo in Japan namely JW-A containing elevated levels of Na. Here, the leach rates increased as a consequence of the radiation damage, due to (a) microcracking at a-doses corresponding to > 104 years of repository storage and (b) atomic displacements within the actinide-bearing phases, zirconolite and perovskite. At high doses, corresponding to > 3 x 104 years of storage, the former process led to leach rate enhancements of about a factor of 10 for Na and Ca, that were a further order of magnitude higher. Modifications to the Synroc composition were devised to prevent microcracking when the Na20 content of the Synroc exceeds ~ 1.5wt%. In the second phase of the Co-operative Program, comparative studies were carried out on Synroc containing Na-free PW-4b waste and in this case, after ~ 105 years of equivalent storage, Sr and Ca leach rates increased by a factor of 10, whereas the leach rate of Ba which is not contained in the actinide host phases did not increase with equivalent storage time. The density decrease due to radiation damage was less in samples stored at 200oC than at 30oC. Complementary studies on Cm-doped single-phase zirconolite and perovskite were carried out and studies on naturally-occurring zirconolites were initiated to provide insight into the long-term durability of zirconolite over geological time. In both phases of the Co-operative Program , the preparation of the Cm-doped samples was carried out in JAERI'S WASTEF facility at Tokai, with technical input and assistance provided by ANSTO where necessary. The results, described in greater detail in this report, have confirmed the potential of Synroc as a second-generation waste form