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Article: Tubulovascular protection from protease-activated receptor-1 depletion during AKI-to-CKD transition
Title | Tubulovascular protection from protease-activated receptor-1 depletion during AKI-to-CKD transition |
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Authors | |
Issue Date | 1-Oct-2023 |
Publisher | Oxford University Press |
Citation | Nephrology Dialysis Transplantation, 2023, v. 38, n. 10, p. 2232-2247 How to Cite? |
Abstract | Background Thromboembolic events are prevalent in chronic kidney disease (CKD) patients due to increased thrombin generation leading to a hypercoagulable state. We previously demonstrated that inhibition of protease-activated receptor-1 (PAR-1) by vorapaxar reduces kidney fibrosis. Methods We used an animal model of unilateral ischemia–reperfusion injury-induced CKD to explore the tubulovascular crosstalk mechanisms of PAR-1 in acute kidney injury (AKI)-to-CKD transition. Results During the early phase of AKI, PAR-1-deficient mice exhibited reduced kidney inflammation, vascular injury, and preserved endothelial integrity and capillary permeability. During the transition phase to CKD, PAR-1 deficiency preserved kidney function and diminished tubulointerstitial fibrosis via downregulated transforming growth factor-β/Smad signaling. Maladaptive repair in the microvasculature after AKI further exacerbated focal hypoxia with capillary rarefaction, which was rescued by stabilization of hypoxia-inducible factor and increased tubular vascular endothelial growth factor A in PAR-1-deficient mice. Chronic inflammation was also prevented with reduced kidney infiltration by both M1- and M2-polarized macrophages. In thrombin-induced human dermal microvascular endothelial cells (HDMECs), PAR-1 mediated vascular injury through activation of NF-κB and ERK MAPK pathways. Gene silencing of PAR-1 exerted microvascular protection via a tubulovascular crosstalk mechanism during hypoxia in HDMECs. Finally, pharmacologic blockade of PAR-1 with vorapaxar improved kidney morphology, promoted vascular regenerative capacity, and reduced inflammation and fibrosis depending on the time of initiation. Conclusions Our findings elucidate a detrimental role of PAR-1 in vascular dysfunction and profibrotic responses upon tissue injury during AKI-to-CKD transition and provide an attractive therapeutic strategy for post-injury repair in AKI. |
Persistent Identifier | http://hdl.handle.net/10722/338828 |
ISSN | 2021 Impact Factor: 7.186 2020 SCImago Journal Rankings: 1.654 |
DC Field | Value | Language |
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dc.contributor.author | Lok, Sarah W Y | - |
dc.contributor.author | Yiu, Wai Han | - |
dc.contributor.author | Zou, Yixin | - |
dc.contributor.author | Xue, Rui | - |
dc.contributor.author | Li, Hongyu | - |
dc.contributor.author | Ma, Jingyuan | - |
dc.contributor.author | Chen, Jiaoyi | - |
dc.contributor.author | Chan, Loretta Y Y | - |
dc.contributor.author | Lai, Kar Neng | - |
dc.contributor.author | Tang, Sydney C W | - |
dc.date.accessioned | 2024-03-11T10:31:51Z | - |
dc.date.available | 2024-03-11T10:31:51Z | - |
dc.date.issued | 2023-10-01 | - |
dc.identifier.citation | Nephrology Dialysis Transplantation, 2023, v. 38, n. 10, p. 2232-2247 | - |
dc.identifier.issn | 0931-0509 | - |
dc.identifier.uri | http://hdl.handle.net/10722/338828 | - |
dc.description.abstract | <p>Background</p><p>Thromboembolic events are prevalent in chronic kidney disease (CKD) patients due to increased thrombin generation leading to a hypercoagulable state. We previously demonstrated that inhibition of protease-activated receptor-1 (PAR-1) by vorapaxar reduces kidney fibrosis.</p><p>Methods</p><p>We used an animal model of unilateral ischemia–reperfusion injury-induced CKD to explore the tubulovascular crosstalk mechanisms of PAR-1 in acute kidney injury (AKI)-to-CKD transition.</p><p>Results</p><p>During the early phase of AKI, PAR-1-deficient mice exhibited reduced kidney inflammation, vascular injury, and preserved endothelial integrity and capillary permeability. During the transition phase to CKD, PAR-1 deficiency preserved kidney function and diminished tubulointerstitial fibrosis via downregulated transforming growth factor-β/Smad signaling. Maladaptive repair in the microvasculature after AKI further exacerbated focal hypoxia with capillary rarefaction, which was rescued by stabilization of hypoxia-inducible factor and increased tubular vascular endothelial growth factor A in PAR-1-deficient mice. Chronic inflammation was also prevented with reduced kidney infiltration by both M1- and M2-polarized macrophages. In thrombin-induced human dermal microvascular endothelial cells (HDMECs), PAR-1 mediated vascular injury through activation of NF-κB and ERK MAPK pathways. Gene silencing of PAR-1 exerted microvascular protection via a tubulovascular crosstalk mechanism during hypoxia in HDMECs. Finally, pharmacologic blockade of PAR-1 with vorapaxar improved kidney morphology, promoted vascular regenerative capacity, and reduced inflammation and fibrosis depending on the time of initiation.</p><p>Conclusions</p><p>Our findings elucidate a detrimental role of PAR-1 in vascular dysfunction and profibrotic responses upon tissue injury during AKI-to-CKD transition and provide an attractive therapeutic strategy for post-injury repair in AKI.</p> | - |
dc.language | eng | - |
dc.publisher | Oxford University Press | - |
dc.relation.ispartof | Nephrology Dialysis Transplantation | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.title | Tubulovascular protection from protease-activated receptor-1 depletion during AKI-to-CKD transition | - |
dc.type | Article | - |
dc.identifier.doi | 10.1093/ndt/gfad051 | - |
dc.identifier.volume | 38 | - |
dc.identifier.issue | 10 | - |
dc.identifier.spage | 2232 | - |
dc.identifier.epage | 2247 | - |
dc.identifier.eissn | 1460-2385 | - |
dc.identifier.issnl | 0931-0509 | - |