Medicine (St Vincent's) - Theses
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ItemTherapeutic effects of phosphodiesterase 4 inhibitor roflumilast in chronic kidney disease( 2016)Progressive chronic kidney disease (CKD) is a major health problem in Australia, and its prevalence is increasing due to the growing incidence of diabetes and hypertension. However, current clinical management of CKD, particularly the use of antihypertensive drugs, and glycaemic control for diabetic patients, is only partially effective against preserving renal function and in delaying end stage kidney disease (ESKD). Therefore, there is a need for new approaches to slow or halt the progression of CKD to ESKD. As chronic inflammation and consequently progressive fibrosis are important features of CKD, this thesis explored the therapeutic potential of phosphodiesterase 4 (PDE4) inhibitor, roflumilast (RFL), a drug has been found to broadly inhibit inflammation, in progressive CKD. Firstly, the efficacy of RFL to inhibit TGF-β1 stimulated effects, where TGF-β1 is a major pro-fibrotic cytokine, was tested in vitro in renal cell cultures. RFL exhibited both anti inflammatory and anti-fibrotic properties, diminishing the expression of pro inflammatory cytokine MCP-1 and weakening TGF-β1 induced pro-fibrotic responses. RFL also normalised cell proliferation changes triggered by TGF-β1 stimulation. However, the mechanism of how PDE4 inhibition by RFL led to the attenuation of these TGF-β1 stimulated effects remains inconclusive, and was at least not solely due to the changes in intracellular cAMP levels. The efficacy of RFL was then investigated in an animal model of progressive CKD, the subtotal nephrectomised rat. RFL treatment attenuated renal decline in this rat model by preserving glomerular filtration rate, reducing proteinuria, and attenuating structural deterioration, such as glomerulosclerosis and tubulointerstitial fibrosis. Moreover, RFL indirectly downregulated TGF-β1 mediated response, implying that the therapeutic effects of RFL may be through a simultaneous inhibition of inflammation and fibrosis than merely through the suppression of inflammation and subsequent attenuation of fibrosis. Finally, the localisation of PDE4 isoforms was investigated in the renal cortex. PDE4 isozymes were mainly localised in the cells of the distal tubules of the tubulointerstitium and the glomeruli. In addition, the expression of PDE4A, PDE4B and PDE4C isozymes in the glomerulus were elevated in the diseased kidney, and colocalised with podocytes. RFL treatment was found to reduce the elevated PDE4 expression, which correlated with the preservation of podocyte number, suggesting that PDE4 inhibition may be relevant in preserving podocyte integrity. In conclusion, it was clearly demonstrated in this thesis that RFL treatment was able to reduce inflammatory and fibrotic processes, in vitro and in an animal model of progressive CKD, and preserve podocyte survival, mechanisms which were independent of hemodynamic changes. Instead, these effects presented by RFL might be through the inhibition of inflammation and TGF-β1 stimulated responses, although the exact mechanism of this remains inconclusive in this thesis. Nonetheless, there is strong basis for use of RFL as a novel therapy to delay the progression of CKD to ESKD. Further investigation on PDE4 inhibition in combination with antihypertensive drugs is necessary to determine potential clinical utility of PDE4 inhibitors in treating CKD.
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ItemTherapeutic potential of the adenosinergic pathway in acute and chronic kidney disease following ischaemia reperfusion injury( 2016)The incidence of chronic kidney disease (CKD) is rising and the consequences of CKD include premature mortality and progression to end stage kidney disease. Renal ischaemia reperfusion injury (IRI) occurring in clinical settings leads to acute kidney injury (AKI) that predisposes to the development of CKD. The hallmark lesion in CKD is renal fibrosis and clinically there is no direct anti-fibrotic therapy available to halt or reverse the development of renal fibrosis. The adenosinergic pathway is activated during renal IRI and the enzyme CD39 is involved in the generation of adenosine, which has been demonstrated to be protective in the acute phase of IRI. This thesis explores the potential of CD39 (either overexpression of a CD39 transgene or administration of soluble apyrase) and the adenosine A2B receptor (A2BR) as therapeutic targets in the reduction of renal fibrosis that develops after the acute phase of IRI. Using mouse models of renal IRI, it was demonstrated that a transient increase in CD39 activity before IRI, by administration of the enzyme apyrase, effectively reduced AKI and renal fibrosis. However, continuously elevated CD39 activity, achieved by overexpression of the human CD39 transgene (CD39Tg), protected against AKI but led to increased renal adenosine content and increased renal fibrosis. Renal fibrosis following IRI was also shown to be associated with increased A2BR mRNA expression in the kidney, and the role of the A2BR in renal fibrosis was examined by administration of a specific A2BR inhibitor. Inhibition of the A2BR following IRI significantly down-regulated a number of signalling molecules that contribute to fibrosis, although no change in fibrosis was demonstrable. While increased adenosine and A2BR activity protect from acute IRI, these studies show that a sustained increase in adenosine levels and increased A2BR expression after IRI promote renal fibrosis. This suggests a dual role for adenosine and the A2BR in renal injury following IRI, which has not previously been recognised. Finally, in a model of unilateral ureteric obstruction (UUO), CD39Tg mice developed a similar extent of fibrosis to that of WT littermates, in contrast to the increased renal fibrosis seen in CD39Tg mice after IRI. These findings indicate that different mechanisms of injury affect different pathways in the development of renal fibrosis. In conclusion, the studies described in this thesis demonstrate that soluble apyrase and A2BR inhibition are potential therapeutic tools to reduce the development of renal fibrosis following IRI. This thesis also highlights the need to identify and understand the multiple pathways involved in the development of renal fibrosis and the possibility that combination therapies will be more effective than single agents in the treatment and prevention of CKD following IRI.