| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 97 === The number of patients on renal replacement therapy due to the progression of chronic kidney disease has gradually increased over the last decades, and the number of patients on renal replacement therapy is predicted to double during the next 10 years. This trend is even more pronounced in Taiwan. Therefore, reduction in the incidence of end-stage renal disease by intervention in early stages of chronic kidney disease to prevent or slow the progression of chronic kidney disease has become important and urgently needed.
Regardless of the initial insults leading to the kidney injury, the degree of inflammation and fibrosis have long been considered as crucial determinants in the progression of kidney diseases and in a long-term prognosis of both human and experimental glomerulonephritis. Therefore, controlling the process of inflammation and fibrosis is a critical step for preserving renal function and preventing the development of end-stage kidney diseases.
We and other investigators have demonstrated that transforming growth factor-β (TGF-β), one of the critical cytokines, plays an important role in tubulointerstitial fibrosis and renal function deterioration by activating its downstream mediators called Smad2/3. In contrast, overexpression of its negative regulator Smad7 is able to block the activation of Smad2/3, thereby inhibiting the pathological effects of TGF-β1, including tubular epithelial-myofibroblast transdifferentiation and renal tubulointerstitial fibrosis. Although the role of TGF-β1 and its downstream Smad signaling in renal fibrosis have been firmly established, the signaling mechanisms of its anti-inflammation activities of TGF-β in kidney diseases are poorly understood. In this thesis, we first tested the hypothesis that TGF-β may signal through its downstream regulator Smad7 to exert anti-inflammatory effect on kidney diseases. This was examined in a rat remnant kidney disease model by using a ultrasound-microbubble-mediated gene transfer of Smad7. In this study, we found that overexpression of renal Smad7 induced IKB-α (a NF.kB inhibitor) expression, thereby inhibiting NF.kB /p65 activation and NF.kB -dependent inflammation, including upregulation of pro-inflammatory cytolines (IL-1β and TNFα) and adhesion molecules (ICAM-1), as well as macrophage and T-cell infiltration, in addition to an inhibition of Smad2/3 phosphorylation and renal fibrosis simultaneously. Thus, the ability of Smad7 to inhibit renal inflammation and fibrosis may represent a new therapeutic strategy for glomerulonephritis.
We also further tested the second hypothesis, that targeting TGF-β/Smad signaling may be a specific and effective therapeutic strategy for chronic kidney disease. This was examined in an immunologically-induced anti-GBM crescentic glomerulonephritis in rats, in which diseased rats were treated with an anti-inflammatory agent-pentoxifylline. In our previous study, we found that epithelial-myofibroblast transition, a critical process in renal fibrosis, was regulated by TGFβ. Therefore, we further hypothesized that the anti-fibrotic effect of pentoxifylline may act by blocking renal TGFβ expression and inactivation of the TGFβ/Smad signaling pathway, a major pathway leading to epithelial-myofibroblast transition and renal fibrosis. Results showed that pentoxifylline treatment blocked the process of epithelial-myofibroblast transition and renal fibrosis in a rat model of anti-GBM crescentic glomerulonephritis. This was associated with inhibition of renal TGFβ expression and inactivation of Smad2/3, demonstrating the TGF-β/Smad signaling pathway as a therapeutic target in kidney diseases.
In conclusion, Smad7 is a therapeutic agent for kidney diseases because Smad7 can inhibit the inflammatory response by inactivating the NF.kB signaling pathway via induction of IkBα, in addition to a protective role in renal fibrosis by blocking the TGF-β/Smad2/3 activation. Pentoxifylline, an anti-inflammatory agent, can also suppress renal fibrosis by blocking the TGF-β/Smad2/3 signaling pathway. Therefore, Smad7 and pentoxifylline may exert their renoprotective effects by blocking both renal inflammation and fibrosis through the TGF-β/Smad signaling pathway. Results from this thesis reveal that targeting the TGF-β/Smad signaling pathway may represent a specific and effective therapeutic strategy for kidney diseases.
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