The global burden of acute kidney injury is approximately 13 million cases a year (Ponce and Balbi, 2016). 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 haemorrhage, is the most common cause of acute kidney injury (Lameire et al., 2006; Lameire and 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). Following short periods of ischaemia, blood flow to the renal cortex largely recovers following reperfusion, but medullary blood flow remains reduced for a prolonged period, especially in the hypoxia-sensitive outer medulla (the organisation of kidney areas and vasculature is shown in our summary Figure 8 below). 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).

Renal no-reflow has been attributed to various causes, including impaired erythrocyte movement and leukocyte accumulation in renal capillaries, as well as increased intratubular pressure (Bonventre and Weinberg, 2003; Sutton et al., 2002; Wei et al., 2017; Yamamoto et al., 2002). However, after years of investigation, no effective treatment is available, even though no-reflow predicts a worse prognosis after kidney ischaemia. We therefore investigated an alternative possible cause of no-reflow, that is ischaemia-evoked contraction of pericytes that regulate capillary diameter, which might reduce renal blood flow and physically trap red blood cells. Indeed, in the brain and heart contractile pericytes on capillaries play a key role in reducing blood flow after ischaemia (Hall et al., 2014; O’Farrell et al., 2017; Yemisci et al., 2009) because capillaries remain constricted by pericytes even when blood flow is restored to upstream arterioles. In the retina it has been shown that this capillary constriction is mediated by α-smooth muscle actin (α-SMA) based actomyosin-mediated contraction of capillary pericytes (Alarcon-Martinez et al., 2019). In the kidney, pericytes are associated with the cortical and medullary peritubular capillaries and the descending vasa recta. As in the retina, pericyte populations in the kidney, particularly those in the descending vasa recta, are associated with α-SMA expression and contractility (Park et al., 1997; Shaw et al., 2018). They play a key role in regulating renal medullary blood flow (Crawford et al., 2012; Pallone and Silldorff, 2001) which is a crucial variable for meeting the contradictory demands of preserving cortico-medullary osmotic gradients to allow water retention in the body, while maintaining adequate oxygen and nutrient delivery. This raises the question of whether pericytes also play a role in generating renal no-reflow after ischaemia.

An important regulator of pericyte contractility is the Rho kinase pathway (Durham et al., 2014; Kutcher et al., 2007), which inhibits myosin phosphatase, thus increasing phosphorylation of myosin light chain (MLC) and increasing contraction (Kimura et al., 1996; Maeda et al., 2003). Overactivity of Rho kinase may play a key role in hypertension and diabetes, as well as in kidney ischaemia (Jahani et al., 2018; Kushiyama et al., 2013; Peng et al., 2008; Soga et al., 2011; Versteilen et al., 2006). Rho kinase may also regulate pericyte contractility by modulating actin polymerisation (Kureli et al., 2020; Kutcher and Herman, 2009; Maekawa et al., 1999; Zhang et al., 2018a). In ischaemia, an important pathway by which Rho kinase inhibits myosin phosphatase is via inactivation of endothelial nitric oxide synthase (eNOS) (Versteilen et al., 2006), thus reducing production of nitric oxide (NO). NO acts on guanylate cyclase to raise the concentration of cyclic GMP, which increases MLC phosphatase activity and thus decreases contraction, so inhibiting eNOS will increase MLC phosphorylation and contraction. Thus, both the direct effect of Rho kinase (Kimura et al., 1996; Maeda et al., 2003) and its actions on eNOS (Versteilen et al., 2006) converge to promote MLC phosphorylation and contraction. Rho kinase is an important effector of vasoconstrictors such as endothelin-1 (Prakash et al., 2008; Wilhelm et al., 1999; Yamamoto et al., 2000) and angiotensin II (Rupérez et al., 2005), but its effects on pericytes are under-studied, although it may control their contractility (Durham et al., 2014; Hartmann et al., 2021; Homma et al., 2014; Kutcher et al., 2007; Pearson et al., 2013).

Few studies have investigated how ischaemia affects renal pericytes (Kwon et al., 2008; McCurley et al., 2017; Zhang et al., 2018b), and whether pericytes contribute to renal no-reflow. However, peritubular pericytes are damaged in cortical tissue of cadaveric renal allografts following ischaemia-reperfusion (Kwon et al., 2008), suggesting that renal blood flow control may be disrupted after ischaemia by pericyte dysfunction. Here, we show that pericyte-mediated capillary constriction, especially of the descending vasa recta, makes a crucial contribution to no-reflow following renal ischaemia and reperfusion. We further show that targeting pericyte-mediated constriction pharmacologically can reduce ischaemia-evoked acute kidney injury.

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. We found in vivo that sites of ischaemia-evoked medullary and cortical capillary block were associated with pericyte locations. Furthermore, after ischaemia and reperfusion, the diameters of descending vasa recta and peritubular capillaries were reduced specifically near pericyte somata, which extend contractile circumferential processes around the capillaries. In contrast, cortical arteriole diameters were not reduced and glomeruli remained perfused. The fact that capillary diameters are reduced specifically near pericyte somata establishes that this is due to a contraction of the circumferential processes of pericytes, and not (for example) due to a decrease in overall perfusion pressure (which would also reduce the diameter of capillaries away from pericyte somata). Together, these data establish pericyte-mediated capillary constriction as a major therapeutic target for treating post-ischaemic renal no-reflow.

Figure 8

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Pericyte-mediated constriction of renal capillaries may reflect reduced Ca²⁺ pumping in ischaemia, raising [Ca²⁺]_i which activates contraction, as for CNS pericytes (Hall et al., 2014). Constriction may also partly reflect a release of angiotensin II (Allred et al., 2000; Boer et al., 1997; da Silveira et al., 2010; Miyata et al., 1999; Sanchez-Pozos et al., 2012; Zhang et al., 2004) and endothelin-1 (Afyouni et al., 2015; Jones et al., 2020; Sanchez-Pozos et al., 2012) which raise [Ca²⁺]_i and Rho kinase activity (Lee et al., 2014; Shimokawa and Rashid, 2007), since we found that blocking endothelin-A receptors and, to a lesser extent, angiotensin II receptors improved post-ischaemic renal blood flow. Consistent with this, it has been demonstrated that vasoconstricting endothelin-A (Crawford et al., 2012; Wendel et al., 2006) and angiotensin II type 1 (AT1) (Crawford et al., 2012; Miyata et al., 1999; Terada et al., 1993) receptors are located on pericytes along the descending vasa recta and regulate contractility at pericyte sites (Crawford et al., 2012). Additionally, endothelin-1 and angiotensin II evoke potent vasoconstriction of the descending vasa recta mainly through endothelin-A (Silldorff et al., 1995) and angiotensin II type 1 (AT1) (Rhinehart et al., 2003) receptors.

It has long been known that some pericyte populations in the kidney, especially those in the descending vasa recta, express α-SMA and regulate capillary blood flow (Park et al., 1997; Shaw et al., 2018), presumably via actomyosin-based contractility. A potentially important physiological role for the presence of α-SMA in the descending vasa recta pericytes is the ability of these pericytes to regulate blood flow distribution within the renal medulla (Pallone and Silldorff, 2001; Park et al., 1997). In cerebral, retinal and cardiac pericytes, demonstrating pericyte α-SMA labelling has been difficult, but a more favourable fixative might increase the percentage of cells labelled (Alarcon-Martinez et al., 2018). In agreement with other studies, we observed that α-SMA protein was strongly labelled within the pericytes surrounding the descending vasa recta (Figure 6k–n; see also Park et al., 1997), including in pericytes near ischaemia-evoked blockage sites. Pericyte-specific deletion of α-SMA would allow assessment of whether this is the actin isoform conferring pericyte contractility (cf. Alarcon-Martinez et al., 2019). Furthermore, ischaemia increased MLC phosphorylation in pericytes (Figure 6a–j) and led to pericyte-mediated capillary constriction, consistent with actomyosin mediating the contractility of these cells.

Rho kinase, a key downstream effector of both endothelin-1 and angiotensin II, inhibits the MLC dephosphorylation required to relax pericytes (Kimura et al., 1996; Maeda et al., 2003), mainly by inhibiting eNOS activity (Versteilen et al., 2006),thus promoting constriction (Hartmann et al., 2021). Rho kinase also promotes actin polymerisation (Kutcher and Herman, 2009; Maekawa et al., 1999; Zhang et al., 2018a). We found that blocking Rho kinase with hydroxyfasudil reduced MLC phosphorylation in pericytes after ischaemia (Figure 6a–j), and reversed ischaemia-evoked pericyte-mediated capillary constriction (hydroxyfasudil increased the capillary diameter specifically at pericyte somata (Figure 4g) in ischaemic animals, implying that the effects of Rho kinase inhibition were on renal pericytes rather than an extra-renal systemic action). This could explain why Rho kinase block reduces acute kidney injury (Kentrup et al., 2011; Prakash et al., 2008; Teraishi et al., 2004; Versteilen et al., 2011; Versteilen et al., 2006), as we have confirmed using kidney injury molecule-1 (Kim-1) as a marker (Figure 7c and d). In addition to inhibiting pericyte-mediated capillary constriction, hydroxyfasudil may also reduce kidney injury by reducing microvascular leukocyte accumulation, possibly by increasing the activity of eNOS (Versteilen et al., 2011; Yamasowa et al., 2005). It will be of interest to assess the efficacy of Rho kinase block for preventing kidney injury after longer periods of ischaemia than the 1 hr that we employed. In agreement with our findings in kidney pericytes, Rho kinase inhibition can block optogenetically induced constriction of brain capillaries by pericytes (Hartmann et al., 2021). Taken together, these findings support the concept that ischaemia-evoked capillary constriction reflects renal pericytes generating an actomyosin-dependent contraction, rather than there being a non-specific mechanism of constriction such as pericyte swelling.

Hydroxyfasudil is the active metabolite of fasudil, a drug that has been clinically approved in Japan since 1995 for the treatment of vasospasm following subarachnoid haemorrhage (Lingor et al., 2019). Fasudil treatment improves stroke outcome in animal models (Vesterinen et al., 2013) and humans (Shibuya et al., 2005) and our data suggest that it may also be useful for reducing post-ischaemic renal no-reflow and kidney damage.

We considered possible non-pericyte explanations for post-ischaemic capillary constriction and block. Post-ischaemic erythrocyte congestion in vasa recta has previously been described (Crislip et al., 2017; Olof et al., 1991) however physically adhering red blood cells do not physically cause the capillary blockages observed after ischaemia as they were associated with only a small percentage of block sites (Figure 4—figure supplement 1a, b). Thus, red blood cell trapping could be a consequence rather than a cause of the blockages. However, we cannot rule out the possibility that we observed only a small percentage of red blood cells in the capillary lumen because they are more readily displaced during the perfusion with PBS and PFA followed by FITC-albumin in gelatin than with protocols that do not perform transcardial perfusion or perform it only once (Gaudin et al., 2014; Yemisci et al., 2009). Leukocyte trapping may also contribute to reducing blood flow, but occurs on a longer time scale than we have studied (Kelly et al., 1994; Rabb et al., 1995; Ysebaert et al., 2000). Similarly, although a degradation of the eGCX has been reported after ischaemia (Snoeijs et al., 2010; Song et al., 2018), we found a uniform distribution of the eGCX along the vessel wall, which was not modified after ischaemia (Figure 4—figure supplement 1e, h), thus ruling out a causal association with capillary blockages which are preferentially located near pericytes. The present study demonstrates that pericyte-mediated constrictions of the descending vasa recta and cortical peritubular capillaries contribute to no-reflow and kidney injury at early stages of reperfusion; however, we cannot exclude the possibility that other factors, such as inflammation and leukocyte infiltration (Gandolfo et al., 2009; Kelly et al., 1994; Rabb et al., 1995; Ysebaert et al., 2000), or eGCX dysfunction (Bongoni et al., 2019), might also contribute to post-ischaemic microvascular injury at later phases of acute kidney injury. Furthermore, in response to the pericyte-mediated constriction evoked by ischaemia, the DVR may undergo post-ischaemic adaptations, releasing more nitric oxide at 48 hr post-ischaemia which could reduce pericyte constriction at later times after ischaemia than we have studied (Zhang et al., 2018b).

The recovery of blood flow in the medulla on renal arterial reperfusion was slower than in the cortex. The regulation of renal medullary blood flow is mainly mediated by vasa recta pericytes, independent of total or cortical blood flow (Pallone and Silldorff, 2001). The need for accurate flow regulation in the relatively hypoxic medulla may account for pericytes on the DVR being much closer together (mean separation 22.9 ± 0.9 µm) and with more circumferential processes (Figure 4a–c, Figure 4—figure supplement 2b) than for peritubular cortical pericytes (mean separation 41.3 ± 2.6 µm) which have mainly longitudinal (strand-like) processes (Figure 5a–c, Figure 4—figure supplement 2a) and this may, in turn, contribute to a greater pericyte-mediated restriction of blood flow after ischaemia in the DVR than in the cortical capillaries. Despite these morphological differences between cortical and medullary pericytes, they showed similar immunoreactivity changes for p-MLC after ischaemia/reperfusion and hydroxyfasudil treatment (Figure 6a–j). Perhaps surprisingly, given our data, in post-cadaveric renal transplants a better outcome has been reported for kidneys with a higher number of pericytes immediately post-transplant (Kwon et al., 2008). This may, however, reflect an aspect of pericyte function other than capillary constriction, such as angiogenesis and maintenance of vessel integrity (Shaw et al., 2018), with these functions failing in transplanted tissue in which pericytes have already died due to ischaemia.

In the brain, heart, and retina, contractile pericytes on capillaries play a key role in producing a prolonged reduction of blood flow after ischaemia (Hall et al., 2014; O’Farrell et al., 2017; Yemisci et al., 2009). Depending on the type of ischaemic model applied to these organs, collateral vessels may allow some (reduced) blood flow after the onset of ischaemia, which would lead to variable organ damage (Farkas et al., 2007; Liu et al., 2019; Minhas et al., 2012). In contrast, the kidney largely depends on the renal artery to provide a non-anastomotic supply to the glomeruli of each nephro-vascular unit (Evans et al., 2013; Pallone et al., 2012). Medullary hypoxia under normal conditions has been documented in several mammalian species, including humans (Epstein et al., 1982; Leonhardt and Landes, 1963). The medullary partial pressure of oxygen is ~10–20 mm Hg, contrasting with the partial pressure of oxygen in the cortex, which is ~50 mm Hg (Brezis et al., 1994a; Brezis et al., 1991; Brezis et al., 1994b). Thus, renal pericytes, especially in the medulla, are likely to be more susceptible to ischaemic injury than in other organs.

Rodent models of renal ischaemia can employ bilateral ischaemia or unilateral ischaemia with or without contralateral nephrectomy (Fu et al., 2018). In the present study, unilateral ischaemia without contralateral nephrectomy (which may occur during renal-sparing surgeries) (Hollenbeck et al., 2006; Medina-Rico et al., 2017) was chosen to explore the early mechanisms of ischaemia and reperfusion injury while using the contralateral kidney as a paired control for potential systemic haemodynamic changes that could be triggered during and after the surgical procedure. The presence of an uninjured contralateral kidney reduces animal mortality during the surgical procedure, and thus longer ischaemia times can be used, resulting in more severe and reproducible injury (Fu et al., 2018; Le Clef et al., 2016; Polichnowski et al., 2020; Soranno et al., 2019). Unilateral ischaemia-reperfusion without contralateral nephrectomy is considered a strong model to study the progression from acute renal injury to long-term tubulo-interstitial fibrosis (Fu et al., 2018; Le Clef et al., 2016; Polichnowski et al., 2020; Soranno et al., 2019), but we acknowledge that the model used in the present study may not be similar to some clinical situations where both kidneys are injured, and there are limitations of translatability from all animal models of acute kidney injury to human disease (Fu et al., 2018). A limitation of our study is that all experiments were performed on male rats and mice. Female rats are relatively protected against post-ischaemic renal failure (Lima-Posada et al., 2017; Müller et al., 2002), possibly because in male rats androgens promote ischaemic kidney damage by triggering endothelin-induced vascular constriction (Müller et al., 2002). However, these studies showed that sex did not influence ischaemia repefusion-induced injury after 24 hr, but only after 7 days (Lima-Posada et al., 2017; Müller et al., 2002), which is on a much longer time scale than we have studied.

In the present study, we have shown that pericyte contraction contributes to reducing cortical and medullary blood flow at early stages of reperfusion. This initial pattern could also contribute to the pericyte injury, detachment and capillary rarefaction observed at later stages after ischaemia and reperfusion (Kramann et al., 2017), which lead to further damage to the kidney (Khairoun et al., 2013; Kramann et al., 2017). However, there was no evidence of pericyte detachment during the time frame of the present study. Treatment from the beginning of reperfusion (to mimic a clinically possible therapeutic approach) with hydroxyfasudil, a Rho kinase inhibitor, increased medullary and cortical blood flow, increased the post-ischaemic diameter of DVR capillaries at pericyte locations, reduced the percentage of DVR capillaries that remained blocked, and reduced kidney injury after renal reperfusion. Presumably, the protection of renal blood flow and downstream tissue health would be even greater if hydroxyfasudil could be given before ischaemia was induced (e.g. in situations such as cardiac surgery and kidney transplantation, where renal ischaemia might be anticipated). Thus, pericytes are a novel therapeutic target for reducing no-reflow after renal ischaemia. Acute kidney injury caused by post-ischaemic no-reflow causes significant socio-economic cost. Our identification ofpericyte contraction as a therapeutic target for ischaemia-induced acute kidney injury should contribute to the development or re-purposing of drugs that can prevent renal no-reflow.

All data generated or analysed during this study are included in the manuscript and supporting file.

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Author details

1. Felipe Freitas

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing

   For correspondence

   f.freitas@ucl.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4627-3509

2. David Attwell

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Conceptualization, Funding acquisition, Project administration, Resources, Supervision, Writing – review and editing

   For correspondence

   d.attwell@ucl.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3618-0843

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