Renal Ischemia‐Reperfusion Impairs Whole Kidney Blood Flow Autoregulation in Male and Female Rats

Abstract

Renal autoregulation is critical in maintaining a stable renal blood flow (RBF) and glomerular filtration rate over a wide range of renal perfusion pressure. Our recent in vitro work demonstrated that accumulating reactive oxygen species (ROS) contribute to loss of renal autoregulatory capability in ischemia reperfusion (IR)‐induced acute kidney injury (IR‐AKI) in male rats. Evidence shows that sex differences might contribute to differential injury in IR‐AKI. Therefore, we hypothesized that renal IR leads to impaired RBF autoregulation which may be associated with ROS accumulation and inflammation in male and female rats. IR was induced by occluding both renal arteries for 60 minutes followed by 24 hours or 1 week of reperfusion. Plasma creatinine was markedly increased in IR rats but more so in males than females at 24 hours (3.8±0.2 vs 1.9±0.4 mg/dl, P<0.05, n=7/group). Plasma creatinine was still elevated in IR males one week post‐IR (1.3±0.1 vs 1.1±0.0 mg/dl in sham, P<0.05, n=13–14/group). Whole kidney autoregulation was assessed in vivo. IR significantly lowered baseline RBF in males (5.9±0.6 vs. 9.1±0.5 ml/min/gkw in sham, P<0.05, n=6/group) but not in females (8.3±0.6 vs. 10.3±0.9 ml/min/gkw in sham, P>0.05, n=5–8/group) 24 hours post‐IR. RBF was lower in IR males compared to IR females (P<0.05). RBF decreased further in IR rats at week 1 (4.1±1.0 ml/min/gkw in males and 4.5±0.2 ml/min/gkw in females, n=2–3). RBF remained constant during stepwise reduction of renal perfusion pressure from 120 to 100 mmHg in both sham males and females at 24 hours and 1 week, indicating intact autoregulation as reflected by autoregulatory index (ARI) between 0.1±0.0 and 0.2±0.1. IR led to impaired RBF autoregulation in males at 24 hours and 1 week, and in females at 24 hours as indicated by ARI between 0.8±0.1 and 1.1±0.2. Interestingly, autoregulation partially recovered in females at week 1 as indicated by ARI of 0.5. Preglomerular microvessels (PGMV) were collected for mRNA measurement (n=4–7 rats/each group). IR increased mRNA expression of p67phox in males at 24 hours (7.3±1.5 vs. 1.1±0.2 in sham, P<0.05) and 1 week (2.2±0.3 vs. 1.0±0.1 in sham, P<0.05). In contrast, IR elevated p67phox mRNA expression in females at 24 hours only (3.9±0.4 vs. 1.5±0.2 in sham, P<0.05) but to a lesser degree compared to IR males (P<0.05). The p47phox mRNA expression was elevated in IR males at 1 week (2±0.3 vs. 1.0±0.1 in sham, P<0.05) but remained unchanged in IR females. IR also markedly increased mRNA expression of MCP‐1 in both male and female rats at 24 hours and 1 week (P<0.05 vs respective sham). TGF‐β mRNA expression tends to increase in IR males at 24 hours and reached statistical significance at week 1 (2.5±0.2 vs 1.1±0.1 in sham, P<0.05). TGF‐β was significantly elevated in IR females though still lower compared to IR males at week 1 (1.7±0.2 vs 2.5±0.2, P<0.05). In conclusion, these results suggest that IR impairs RBF autoregulation in male and female rats which might be associated with activation of NOX, MCP‐1 and TGF‐β pathways in PGMV. Female rats have less kidney injury which might be attributed to less NOX expression in PGMV.Support or Funding InformationThis study was supported by grants from NIH (DK106500) to ZG, and NIH (DK044628 and HL095499) to EWI.