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Potential Anti-Fibrotic Effects of MMP-2 and -9 inhibitor 1, Pepstatin A and Calpeptin in Human Precision-Cut Kidney Slices

Tangerman, Meindert (2021) Potential Anti-Fibrotic Effects of MMP-2 and -9 inhibitor 1, Pepstatin A and Calpeptin in Human Precision-Cut Kidney Slices. Research Project 1, Biomedical Sciences.


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Introduction: In an attempt to broaden the donation pool there has been a lot of interest in DCD kidney in recent years. DCD are usually inferior to DBD kidneys since they often undergo a serious warm ischemic injury. Previous research showed increased expression of matrix metalloproteinases 2 and 9, cathepsins D&L and calpains 1&2 during warm ischemic injury. These are all proteases involved in the microinflammatory response that drives IRI. Inhibition of these proteases could decrease the inflammatory and pro-fibrotic response, and ultimately increased graft survival of DCD kidneys. The aim of this study is to identify the anti-fibrotic effect of MMP2/9, Cathepsin D/L and Calpain1/2 inhibition using human precision-cut kidney slices. Materials: Human kidney tissue was gathered at the O.R. after a nephrectomy. Precision cut kidney slices were used to study the anti-fibrotic effects of MMP-2/-9 inhibitor 1, Pepstatin A (Cathepsin D&L inhibitor) and Calpeptin (Calpain 1&2 inhibitor) after 24 and 48 hours of incubation at 37°C. Viability was assessed with ATP analysis and collagen deposition was estimated with a Sirius red stain. Tissue damage was analysed with a PAS stain, based on glomerular structures, tubular dilatation and tubular necrosis. Results: All treated slices maintained viability during 48 hours of incubation, but did not show any significant difference with control after either 24 or 48 hours of incubation. Histological analysis with a PAS stain did not show a significant difference between treated and untreated slices in glomerular structures, tubular dilatation and acute tubular necrose. A Sirius red stain suggested in increase in collagen type 1 deposition in slices treated with MMP-2/-9 inhibitor 1, but showed contradictory results in slices treated with Pepstatin A and Calpeptin Conclusion: None of the inhibitory compounds appeared to have an anti-fibrotic effect on human precision cut tissue slices. More research needs to be done to explain deviations in results after MMP-2/-9-, Cathepsin D&L- and Calpain 1&2 inhibition.

Item Type: Thesis (Research Project 1)
Supervisor name: Leuvenink, H.G.D. and Leeuwen, L.L. van
Degree programme: Biomedical Sciences
Thesis type: Research Project 1
Language: Dutch
Date Deposited: 06 Aug 2021 05:57
Last Modified: 11 Aug 2021 13:21

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