High-mobility group box 1 impairs renal microvascular autoregulatory responses in male and female rats

Abstract

High-mobility group box 1 (HMGB1) is a nuclear protein that functions as a paracrine signaling molecule when released from the nucleus of stressed or injured cells into the interstitial fluid. Secreted HMGB1 can activate toll-like receptor 4 (TLR4) and we showed that activation of renal TLR4 causes autoregulatory dysfunction. In addition, microvascular function is seriously compromised in hypertension but the specific mechanisms involved are poorly defined. We tested the hypothesis that HMGB1 negatively influences renal microvascular autoregulatory capability by activating TLR4. Experiments were performed in male rats using the blood-perfused juxtamedullary nephron technique. Three groups were studied: control, HMGB1 (~1.25 μg/ml in the blood perfusate) and HMGB1+LPS-RS (TLR4 blocker; ~10 μg/ml in the blood perfusate). Afferent arteriole autoregulatory behavior was assessed in these groups by increasing perfusion pressure from 65 to 170 mmHg in 15 mmHg increments. Starting diameters of male arterioles, measured at 100 mmHg, were similar across all three groups (15.3±0.7; 15.1±0.2 and 15.3±0.1 μm, respectively). When perfusion pressure increased from 65 to 170 mmHg, control arteriole diameter decreased to 69±3% of baseline (P<0.05; n=6), exhibiting normal pressure-induced autoregulatory vasoconstriction. Afferent arteriole diameters in kidneys receiving HMGB1 remained unchanged at 97±1% over the same pressure range (n=9; P>0.05 vs. baseline; P<0.05 compared to control kidneys), indicating significant loss of autoregulatory behavior. In the HMGB1+LPS-RS group, afferent arteriole responses were similar to normal controls and decreased to 76±1% (n=6; P<0.05 vs baseline; P<0.05 vs. HMGB1) over the same pressure range, signifying normalization of autoregulatory behavior by TLR4 blockade. There are few published data on the response of female afferent arterioles to the change in perfusion pressure, so we conducted separate experiments using females in two groups of rats, (normal kidneys with or without HMGB1 in the perfusate blood). Baseline diameters of female arterioles (100 mmHg) were similar across both groups (14.7±0.4 and 14.2±0.3 μm, respectively) and were similar to baseline diameters in males (P>0.05). Increasing perfusion pressure from 65 to 170 mmHg decreased female control arteriole diameter to 78±1% (P<0.05 vs baseline; n=6), reflecting normal autoregulatory vasoconstriction resembling that observed in males. Afferent arteriole diameters in female kidneys receiving HMGB1 actually became slightly larger to 103±1% (P<0.05 vs baseline; P<0.05 vs control kidneys; n=6) by 170 mmHg, indicating significant loss of autoregulatory reactivity and that female renal microvessels respond to HMGB1 similarly to males. These data demonstrate that HMGB1 exposure can impair afferent arteriole autoregulatory capability in male and female rats and suggests that impairment involves HMGB1-dependent TLR4 activation. Study supported by NIH (DK044628). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.