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Ischemia‐induced vascular congestion of the ascending vasa recta precedes congestion of the peritubular capillaries in the renal medulla

Vascular congestion, or the aggregation of red blood cells in the microvasculature of the renal medulla is a prominent finding in ischemic acute kidney injury (AKI). Studies in rodent models of ischemia‐reperfusion injury (IRI) have suggested that vascular congestion occurs during the ischemic period and worsens following reperfusion, however, the location(s) in which congestion originates during ischemia have not been defined. We hypothesized that ‘vascular congestion first occurs in the medullary vasa recta (VR) capillaries during the ischemic period, prior to congestion of peritubular (PT) capillaries during reperfusion’. To test this hypothesis, a 45‐minute warm bilateral ischemia was performed in male WKY rats (10 wks old). Rats were randomized to 0, 1, 2, 6, 10, or 24 hour(s) of reperfusion (n=5/group). Congestion of the cortical PT capillaries, medullary VR and PT capillaries, and inner medulla (IM) was scored (blinded; scale: 0–5, 0=0% congestion, 5=100% congestion) in histological sections. To localize congestion within the VR, immunofluorescence of neural‐glial antigen 2 (NG2) was assessed. Medullary VR congestion score was 4.5 (90%) at time 0 (no reperfusion) and remained elevated at 1–10 hours of reperfusion. At 24 hours of reperfusion, VR congestion had significantly decreased to 30% (pANOVA= 0.004, post hoc p=0.002). Medullary PT congestion score was 0.5 (10%) at time 0 and was significantly less than the VR congestion at time 0 (90%) (pINTERACTION=0.004, post hoc p<0.0001). Non‐quantitative analysis of NG2 staining, localized congestion to the ascending VR. At time 0, IM congestion score was 0.5 (10%). IM congestion increased to 4 (80%) by 2 hours of reperfusion (pANOVA=0.022, post hoc p=0.019) and remained elevated through 10 hours of reperfusion, however by 24 hours of reperfusion IM congestion had decreased. Congestion of the cortical PT capillary congestion was significantly greater at time 0 and had an average score of 2.5 (50%) (pANOVA=0.0005). Following 1, 2, or 6 hour reperfusion, cortical PT congestion decreased to less than 10%, and with 10 or 24 hour reperfusion there was no cortical congestion. It has been reported that congestion occurs during ischemia and increases following reperfusion, however the localization of medullary congestion over the initial 24 hours of reperfusion remains unknown. Importantly, our data provides the first evidence that medullary congestion originates in the VR capillaries during the ischemic period and is evident prior to congestion in the PT capillaries during reperfusion. Pericytes are contractile cells which surround the descending vasa recta (DVR). Using a pericyte marker, NG2, we found that congestion was not in NG2‐positive DVR but was localized to the ascending VR (NG2‐negative). Vascular congestion of the renal medulla has been reported to be the primary factor contributing to non‐recovery from ischemic AKI. Understanding how, and where, congestion occurs in the renal medulla is critical to find therapeutic targets for congestion in order to improve recovery from ischemic AKI. We speculate that medullary congestion of AVR may drive blood into the PT capillaries during reperfusion where it then becomes trapped which may prolong ischemia and worsen injury.