Pericyte-mediated constriction of renal capillaries evokes no-reflow and kidney injury following ischaemia
Curation statements for this article:-
Curated by eLife
Evaluation Summary:
This paper extends our understanding of blood flow regulation in the ischemic kidney and adds to a growing body of literature on the role played by pericyte contraction in the aftermath of ischemia/reperfusion (much of it based on the CNS microvasculature), and the potential of capillary pericytes as therapeutic targets in mitigating ischemia/reperfusion injury. This is an important study which should be of interest to a wide variety of investigators in vascular and renal biology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
- Medicine (eLife)
Abstract
Acute kidney injury is common, with ~13 million cases and 1.7 million deaths/year worldwide. A major cause is renal ischaemia, typically following cardiac surgery, renal transplant or severe haemorrhage. We examined the cause of the sustained reduction in renal blood flow (‘no-reflow’), which exacerbates kidney injury even after an initial cause of compromised blood supply is removed. Adult male Sprague-Dawley rats, or NG2-dsRed male mice were used in this study. After 60 min kidney ischaemia and 30–60 min reperfusion, renal blood flow remained reduced, especially in the medulla, and kidney tubule damage was detected as Kim-1 expression. Constriction of the medullary descending vasa recta and cortical peritubular capillaries occurred near pericyte somata, and led to capillary blockages, yet glomerular arterioles and perfusion were unaffected, implying that the long-lasting decrease of renal blood flow contributing to kidney damage was generated by pericytes. Blocking Rho kinase to decrease pericyte contractility from the start of reperfusion increased the post-ischaemic diameter of the descending vasa recta capillaries at pericytes, reduced the percentage of capillaries that remained blocked, increased medullary blood flow and reduced kidney injury. Thus, post-ischaemic renal no-reflow, contributing to acute kidney injury, reflects pericytes constricting the descending vasa recta and peritubular capillaries. Pericytes are therefore an important therapeutic target for treating acute kidney injury.
Article activity feed
-
-
Evaluation Summary:
This paper extends our understanding of blood flow regulation in the ischemic kidney and adds to a growing body of literature on the role played by pericyte contraction in the aftermath of ischemia/reperfusion (much of it based on the CNS microvasculature), and the potential of capillary pericytes as therapeutic targets in mitigating ischemia/reperfusion injury. This is an important study which should be of interest to a wide variety of investigators in vascular and renal biology.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their names with the authors.)
-
Joint Public Review:
In this manuscript, Freitas and Attwell use a rat model of renal ischemia and reperfusion to investigate the cellular and molecular basis of acute kidney injury that follows renal ischemia/reperfusion, such as occurs in certain clinical settings, including cardiac surgery, renal transplantation and severe hemorrhage. They found that the long-lasting "no-flow" phenomenon that develops under these conditions is attributable to contraction of pericytes in descending vasa recta and peritubular capillaries, without the involvement of glomerular arterioles. Using a pharmacological approach, they further demonstrated that perfusion during the reperfusion phase was normalized in the cortex and increased relative to controls in the medulla by the selective RhoA/Rho kinase (ROCK) inhibitor, hydroxyfasudil (HF). The authors …
Joint Public Review:
In this manuscript, Freitas and Attwell use a rat model of renal ischemia and reperfusion to investigate the cellular and molecular basis of acute kidney injury that follows renal ischemia/reperfusion, such as occurs in certain clinical settings, including cardiac surgery, renal transplantation and severe hemorrhage. They found that the long-lasting "no-flow" phenomenon that develops under these conditions is attributable to contraction of pericytes in descending vasa recta and peritubular capillaries, without the involvement of glomerular arterioles. Using a pharmacological approach, they further demonstrated that perfusion during the reperfusion phase was normalized in the cortex and increased relative to controls in the medulla by the selective RhoA/Rho kinase (ROCK) inhibitor, hydroxyfasudil (HF). The authors conclude that ROCK-dependent contraction of capillary pericytes is responsible for the observed long-lasting decrease in blood flow in the kidney upon ischemia/reperfusion.
Support for capillary pericyte contraction is largely descriptive - imaging in kidney slices from NG2-DsRed mice perfused with a FITC-albumen/gelatin solution showing reduced capillary diameter near NG2-labeled cells combined with a quantitative analysis of the distribution of blockage-pericyte distances. Data obtained using HF provides additional indirect support for the centrality of pericyte contraction/relaxation, showing that HF increases capillary blood flow, increases capillary diameter in the vicinity of pericytes, and does not affect the diameter of glomerular arterioles.
-
