Kidney Week

Abstract: SA-PO089

Greater High-Mobility Group Box 1 (HMGB1) in Male Spontaneously Hypertensive Rats (SHR) Enhances Renal Ischemia-Reperfusion (IR) Injury Compared with Females

Session Information

• AKI: Mechanisms - Primary Injury and Repair - II
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Mohamed, Riyaz, Augusta University, Medical College of Georgia, Augusta, Georgia, United States

Riyaz Mohamed,

• Rafikova, Olga, University of Arizona, Tucson, Arizona, United States

Olga Rafikova,

• O'Connor, Paul, Augusta University, Medical College of Georgia, Augusta, Georgia, United States

Paul O'Connor,

• Sullivan, Jennifer C., Augusta University, Medical College of Georgia, Augusta, Georgia, United States

Jennifer C. Sullivan,

Background

Renal IR injury is a major cause of acute kidney injury, which carries a high mortality rate and increases the risk of later developing hypertension and CKD. There are sex differences in renal IR injury, with males exhibiting greater injury following an ischemic insult than females. The mechanisms that are responsible for observed sex differences in IR injury are unknown. Recent studies have reported that increased HMGB1 after renal IR in males contributes to renal damage. The contribution of HMGB1 to renal IR injury in females is unknown. We hypothesis that greater HMGB1 in males promotes enhanced renal IR injury compared to females.

Methods

13wk old male and female SHR were subjected to sham or 45-min warm bilateral ischemia followed by 24hr reperfusion. A separate set of SHR were pre-treated with control (IgG) or neutralizing anti-HMGB1 antibody (300 µg/rat) 1hr prior to renal IR (n=4-6). Blood was collected for biochemical analysis; kidneys were harvested for histological and WB analysis.

Results

IR significantly increased renal HMGB1 levels in both sexes compared to sham (P_IR<0.001). Renal HMGB1 levels were greater in males vs. females, although the effect of IR to increase HMGB1 levels was comparable between the sexes (P_sex= 0.009, P_sex*IR=0.3). Treatment with anti-HMGB1 ab prior to IR attenuated IR-induced increases in plasma creatinine (P_anti-HMGB1=0.02), tubular damage (P_anti-HMGB1=0.04), and tubular cell death (P_anti-HMGB1=0.04) compared to rats receiving control IgG. However, effect of anti-HMGB1 ab was only observed in males; treatment with anti-HMGB1 did not alter plasma creatinine (P_sex=0.1; P_{sex*anti-HMGB1}=0.0039), tubular damage (P_sex=0.99; P_{sex*anti-HMGB1}<0.003) and tubular cell death (P_sex=0.07; P_{sex*anti-HMGB1=}0.05) following IR in females. In addition, HMGB1 neutralization attenuated IR-induced activation of pro-inflammatory signaling molecules downstream of HMGB1 only in male SHR, including decreased renal Toll-like receptor (TLR) 4 phosphorylation (P_anti-HMGB1=0.08; P_sex*_anti-HMGB1=0.004), IL1β mRNA (P_anti-HMGB1=0.04; P_sex*_anti-HMGB1=0.05) and plasma TNFα (P_anti-HMGB1=0.61; P_sex*_anti-HMGB1=0.03).

Conclusion

In conclusion, greater levels of HMGB1 in males compared to females results in enhanced pro-inflammatory signaling and exacerbation of IR-induced injury.

Funding

• Other NIH Support