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Title: Elucidating the mechanisms of Gremlin 1-mediated bone morphogenetic protein antagonism and acute kidney injury in vivo
Author: Church, Rachel Henrietta
ISNI:       0000 0004 5994 9915
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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Diabetic nephropathy (ON) is a major microvascular complication associated with diabetes. DN is characterised by a progressive loss in renal function and associated renal fibrosis. Currently, no cure exists for DN and therapeutic strategies seek to slow the decline in renal function, through glycaemic and blood pressure control. Acute kidney injury (AKI) is a condition that can arise due to a range of pre-renal, renal and post- renal causes. AKI is associated with decreased glomerular filtration rate (GFR), resulting in accumulation of nitrogenous waste products and other complications. The precise molecular mechanisms of renal damage in these diseases is still not fully understood and needs to be further elucidated. Bone morphogenetic proteins (BMPs) have been shown to be anti-fibrotic in models of renal fibrosis. Gremlin1 (Grem1), a BMP antagonist is upregulated in conditions such as ON. It is hypothesised that Grem1 binding to BMPs is crucial to its pathogenic role in renal fibrosis. The specific interactions of Grem1 and BMPs in disease have not been fully determined. The overarching aim of this thesis was to better define the role of Grem1 binding to BMPs in vitro, in order to contribute to our understanding of these interactions in the context of kidney disease. Using a range of in vitro methods, we determined that Grem1 relative binding affinity is BMP-2>-4>-7, and that the post-translational modifications of glycosylation and phosphorylation of Grem1 may not be essential for BMP antagonism. We also found that Grem2 differentially inhibits BMP-2, -4 and -7 signalling in vitro. We determined that isolation of Grem1-BMP complexes are difficult using standard in vitro methods, and that direct mass spectrometry (MS) approaches may be advantageous. We have determined that mice with tubular specific deletion of Grem1 (Grem1 TEC -1-) display somewhat attenuated renal damage in a folic acid (FA) induced model of AKI. These findings provide a mechanistic insight into the possible molecular interactions between Grem1 and BMPs, and may have implications in the context of renal fibrosis. Given the high binding observed between Grem1 and BMP-2, this complex formation may be favoured in the 'diseased' kidney. Furthermore, Grem1 inhibition of BMP-7 may not occur via direct interaction. Manipulation of the Grem1-BMP axis has been explored as a potential therapeutic strategy by many research groups, and this is further supported by our findings that Grem1 TEC -1- mice display attenuated renal injury in a model of AKI. Further work will be required to further define these interactions in models in renal fibrosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available