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Title: Can the inhibition of TAFI affect kidney plasmin activity, ECM accumulation and the progression of experimental chronic kidney disease?
Author: Atkinson, John
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2013
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Chronic kidney disease (CKD) is characterised by the pathological accumulation of extracellular matrix (ECM) proteins leading to progressive kidney scarring via glomerular and tubular basement membrane expansion. Increased ECM synthesis and deposition, coupled with reduced ECM breakdown contribute to the elevated ECM level in CKD. Previous pre-clinical studies have demonstrated that increased plasmin activity has a beneficial effect in the protein overload model of CKD. As plasmin activation is down regulated by the action of the thrombin activated fibrinolytic inhibitor (TAFI), we tested the hypothesis that inhibition of TAFI might increase plasmin activity & reduce ECM accumulation in an in vitro model of glucose induced ECM expansion. Treatment of NRK52E tubular epithelial cells with increasing concentrations of glucose resulted in a 40% increase in TAFI activity, a 38% reduction in plasmin activity and a subsequent increase in ECM accumulation. In this model system, application of the previously reported TAFI inhibitor UK-396082 [(2S)-5-Amino-2-[(1-n-propyl-1H-imidazol-4-yl)methyl]pentanoic acid] caused a reduction in TAFI activity, increased plasmin activity and induced a parallel decrease in ECM levels. In contrast, RNAi knockdown of plasmin resulted in an increase in ECM levels. An evaluation of serum TAFI and plasmin activity from individuals with CKD indicated a strong correlation between elevated TAFI and reduced plasmin levels with renal impairment. These findings correlated with similar observations made in the rat following sub-total nephrectomy. Pharmacological inhibition of TAFI with UK-396082 reduced glomerular and tubulointerstitial ECM deposition. Renal function, as measured by an increase in creatinine clearance and decrease in proteinuria, and survival improved with TAFI inhibition. Taken together, the data support the importance of the fibrinolytic axis in regulating renal fibrosis and point to a potentially important therapeutic role for TAFI inhibition.
Supervisor: Johnson, Tim Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available