Pretreatment with low dose lipopolysaccharide promotes rapid decongestion of medullary capillaries
Authors: Ray Sarah Corine , Sun Jingping , O'Connor Paul 
Published: April 2020

Acute kidney injury (AKI) is common and has a mortality rate as high as 60%. Vascular congestion is a hallmark of AKI and is the aggregation of red blood cells (RBC) in the capillaries of the renal medulla following ischemia. Studies have shown that the severity of vascular congestion directly correlates with the recovery of renal function following ischemia. We recently reported that pretreatment with low dose lipopolysaccharide (LPS) attenuates vascular congestion following ischemia‐reperfusion injury (IRI) in rats. It remains unknown, however, if LPS prevents the formation of congestion or aids in the clearance of congestion following reperfusion. We hypothesized that ‘low dose LPS stimulates the clearance of RBC aggregates during early reperfusion’. To test this hypothesis, male WKY rats (10wks) were pretreated (i.p) with 1000μg/kg LPS (serotype O111:B4) or saline daily for 3 days. Following pretreatment, a 45‐minute warm, bilateral ischemia was performed. Rats were randomized to either 0, 1, 2, 6, 10, or 24 hour(s) of reperfusion (n=4/group). Following reperfusion, blood was collected for measurement of erythrocyte sedimentation rate (ESR). Congestion of the medullary vasa recta (VR) and peritubular (PT) capillaries was assessed in histological sections (blinded, scale: 0–5, 0=0% congestion, 5=100% congestion). Medullary VR congestion was not different between saline and LPS treated rats at time 0 (no reperfusion) with a score of 4 (80%) for both. Following reperfusion for 1, 2, 6, and 10 hours, VR congestion in saline treated rats remained elevated (average score: 4.09). In contrast, in LPS treated rats, VR congestion rapidly declined (within 1 hour), such that between 1–10 hours of reperfusion VR congestion averaged 1.89 (pTREATMENT<0.0001). PT congestion was minimal for both saline and LPS treated rats at time 0 (no reperfusion) but rapidly increased in saline treated rats to >60% at 6 hours. Conversely, in LPS treated rats PT congestion remained low (average 13.4%, pINTERACTION=0.0144) across the 24 hour reperfusion period. In saline treated rats, ESR, which is a marker of inflammation, was less than 2mm at 1–10 hours of reperfusion but increased to 7mm at 24 hours post‐ischemia. In LPS treated rats, ESR increased in a time dependent manner from 0mm at time 0 to 10mm at 24 hours (pTREATMENT<0.0001). We recently reported that pretreatment with LPS reduced vascular congestion 24 hours following ischemia‐reperfusion, however it was unclear whether LPS prevents the development of congestions or contributes to a quicker reperfusion. In this study, we tracked congestion following different hour(s) of reperfusion and found that LPS aids in flushing the VR following reperfusion which prevents the development of PT congestion. We speculate the early immune response evoked by LPS pretreatment, evident by ESR, is responsible for the rapid clearance of congestion in these animals. Understanding the mechanism by which LPS promotes this protective response to attenuate renal medullary congestion following ischemia may provide new methods to improve recovery and mortality rate from ischemic AKI.

Support or Funding Information

NIH PO1HL134604 and DK099548