Medicine (St Vincent's) - Theses
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ItemFibrosis in experimental diabetic nephropathy and cardiomyopathy: effects of FT011, a novel anti-fibrotic intervention( 2011)It is estimated that by 2025, 366 million people worldwide will be diagnosed with diabetes mellitus (DM); this brings with it the potential for an increase in the prevalence of diabetic nephropathy (DN) and cardiomyopathy (DCM). Despite current management for diabetes, DN is the leading cause of end stage of kidney disease (ESKD) for renal replacement therapy, and DCM is associated with a higher incidence of chronic heart failure (CHF). Pathological fibrosis is a hallmark of progressive renal and cardiac disease leading to ESKD and CHF. Growth factors such as transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) have been consistently implicated in the fibrogenesis in DN and DCM. Therefore, strategies inhibiting the bioactivities of these cytokines are becoming valuable anti-fibrotic therapeutic targets. Tranilast is one of series compounds that have been shown to inhibit actions of TGF-β and PDGF. To optimise the anti-fibrotic effects of tranilast, FT011 (Fibrotech Therapeutics, Pty. Ltd, Melbourne, Australia) is a newly synthesized compound based on cinnamoyl core structure of tranilast. The hypothesis of the thesis is that targeted treatment for fibrosis with FT011 will attenuate functional and structural manifestations of injury in experimental DN and DCM. The aims of this thesis were to firstly evaluate the inhibitory effects of FT011 on collagen synthesis and cell proliferation in vitro and in vivo models, and then to explore therapeutic effects of FT011 in experimental DN and DCM. In cultured rat mesangial cells, FT011 inhibited TGF-β1 and PDGFBB induced collagen production and cell proliferation in a dose dependent manner with no evidence of cell toxicity. Consistent with these actions, treatment of anti-Thy1 nephritis with FT011 attenuated matrix accumulation, mesangial phenotypic changes, mesangial cell proliferation and glomerular macrophage infiltration. These findings suggest a promising profile of FT011 for its potential use as an anti-inflammatory and anti–fibrotic drug. Progressive DN is characterised by glomerulosclerosis and tubulointerstitial fibrosis leading to capillary rarefaction with consequent loss of renal parenchyma and function. Both early and late intervention with FT011 in diabetic Ren-2 rats, a clinically predictive experimental model of DN, prevented development of albuminuria, tubulointerstitial fibrosis, and glomerulosclerosis. In addition, treatment of diabetic Ren-2 rats with FT011 was associated with a reduction in loss of glomerular capillary endothelial cells, interstitial macrophage accumulation and tubular cell apoptosis. These findings prove the hypothesis that targeted treatment for fibrosis with FT011 would attenuate renal functional and structural injury in experimental DN. Pathologically, DCM is associated with microvascular disease and characterised by myocyte hypertrophy, apoptosis and accumulation of interstitial matrix. These structural changes ultimately lead to heart dysfunction. Treatment of diabetic Ren-2 rats with FT011 attenuated systolic and diastolic dysfunction associated with reduction in interstitial fibrosis and myocyte hypertrophy. These findings prove the hypothesis that anti-fibrotic and anti-hypertrophic therapy with FT011 would attenuate heart dysfunction in DCM. The anti-fibrotic effects of FT011 observed in diabetic kidney and heart are independent of changes in high blood pressure and glucose, and the anti-fibrotic therapeutic efficacy of FT011 is greater than previous studies with tranilast. In addition, treatment with FT011 reduced ERK1/2 MAP kinase phosphorylation in both the diabetic kidney and heart. These findings suggest that anti-fibrotic mechanism actions of FT011 are different from blood pressure and glucose lowering agents and may be attributable to events that are more down stream signalling pathways of TGF-β, although the precise mode of action for FT011 was not determined in the present thesis. In conclusion, the findings of the present thesis advocate the use of strategies that target treatment for fibrosis by inhibiting bioactivities of pro-fibrotic cytokines delays the progression of DN and DCM. These findings yield important preclinical information in terms of the potential utility of FT011 as a novel anti-fibrotic therapy in the treatment of DN and DCM.