Pericyte-mediated constriction of renal capillaries evokes no-reflow and kidney injury following ischaemia.

Felipe Freitas,David Attwell

doi:10.7554/elife.74211

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.

Highlights

The global burden of acute kidney injury is approximately 13 million cases a year (Ponce &Balbi, 2016)
Renal ischaemia followed by reperfusion, which can occur after cardiac surgery, renal transplant or severe hemorrhage, is the most common cause of acute kidney injury (Lameire et al, 2006; Lameire & Vanholder, 2001)
This paper demonstrates, for the first time, that the long-lasting decrease of renal blood flow that follows transient ischaemia is generated by pericyte-mediated constriction and block of the descending vasa recta and cortical peritubular capillaries, as schematised in the summary of Figure 8, and that this post-ischaemic no-reflow can be reduced pharmacologically

Summary

Introduction

The global burden of acute kidney injury is approximately 13 million cases a year It is associated with a high mortality (1.7 million deaths per year, worldwide) (Gameiro et al, 2018; Hoste et al, 2018; Mehta et al, 2016), and COVID-19 has added to its incidence (Ronco et al, 2020). Renal ischaemia followed by reperfusion, which can occur after cardiac surgery, renal transplant or severe hemorrhage, is the most common cause of acute kidney injury (Lameire et al, 2006; Lameire & Vanholder, 2001). Sustained renal blood flow reductions occur after ischaemia and reperfusion, both in experimental studies and in patients after kidney transplantation (Cristol et al., 1996; Nijveldt et al, 2001; Ramaswamy et al, 2002). Medullary no-reflow is a critical event for amplifying renal tissue injury following reperfusion (Conesa et al, 2001; Olof et al, 1991; Regner et al, 2009)

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