Medicine (St Vincent's) - Theses
Permanent URI for this collection
Search Results
1 - 1 of 1
-
ItemThe role of activin and follistatin in ischaemia-reperfusion-induced acute and chronic kidney injury( 2023-05)The incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) is rising and presents a major economic burden in Australia and globally. AKI and CKD, once regarded as two distinct syndromes, are now increasingly recognised as interconnected syndromes and likely to promote one another. An episode of AKI, even with biochemical recovery, increases the risk of future CKD. Likewise, underlying CKD is an important risk factor for AKI. Both AKI and CKD are associated with increased morbidity and mortality, including major cardiovascular events, progression to kidney failure requiring kidney replacement therapy (KRT), and premature death. Kidney ischaemia-reperfusion injury (IRI) is one of the leading causes of AKI and predisposes to the development of CKD. In kidney transplantation, IRI is an inevitable event and has a negative impact on both short and long-term graft survival. Regardless of the initial trigger of injury to the native or transplanted kidneys, fibrosis is the characteristic pathological change and final common pathway of progressive CKD. To date, available therapies slow the progression of fibrosis but there remains no effective clinical treatment to prevent or reverse kidney fibrosis. Therefore, attenuation of IRI to reduce the severity of AKI and subsequent development of CKD and kidney failure is an important area of research. Activin A has been implicated as a key driver of inflammation and fibrosis. Similar roles are now emerging for activin B. Follistatin (FS) is an activin-binding protein that counters the action of activins. This thesis examined the role of activin A and B in ischaemia-reperfusion (IR)-induced inflammation and fibrosis, and the therapeutic potential of FS in mitigating AKI and CKD. Using mouse models of kidney IRI, we demonstrated a significant increase in activin A and B levels, albeit with different kinetics, following kidney IR, with an associated increase in the expression of pro-inflammatory cytokines and evidence of AKI. FS treatment given pre-ischaemia reduced activin levels and inflammation, and attenuated IR-induced AKI. FS treatment also attenuated IR-induced kidney fibrosis when given in the early period post-IR on day 3 to 5. Together, these findings suggested that activin A and B are likely involved in promoting IR-induced AKI as well as CKD. The activin antagonist FS is a promising therapy in reducing the severity of AKI and subsequent development of CKD.