Acute Antioxidant Treatment Restores Afferent Arteriole Autoregulatory Behavior in Ischemia‐Reperfusion Acute Kidney Injury Rats

Renal autoregulation plays a critical role in maintaining a stable renal blood flow and glomerular filtration. Our recent studies indicated that excess reactive oxygen species (ROS) contribute to renal autoregulatory dysfunction in ischemia‐reperfusion (IR) induced acute kidney injury (IR‐AKI) rats. We hypothesized that antioxidant treatment would improve renal autoregulatory behavior in IR‐AKI rats possibly through inhibition of superoxide and/or hydrogen peroxide production. IR was induced with 60‐minute bilateral renal artery occlusion followed by 24 hours of reperfusion. Autoregulatory function of afferent arterioles was assessed in vitro using the blood‐perfused juxtamedullary nephron preparation. Afferent arterioles from sham control rats exhibited pressure‐dependent vasoreactivity (n=7). Baseline arteriole diameter averaged 13.2 ± 0.4 μm and increased significantly to 114 ± 4% of the baseline (P<0.05) after decreasing perfusion pressure to 65 mmHg. Step increases in perfusion pressure (15 mmHg intervals) decreased diameter to 65 ± 3% of the baseline at 170 mmHg (P<0.05 vs. baseline), indicating intact renal autoregulation. In contrast, pressure‐mediated afferent arteriole responses were significantly attenuated in IR rats (n=8). Baseline diameter averaged 11.7 ± 0.5 μm and remained between 90 and 101% of baseline over the 65–170 mmHg pressure range tested (P>0.05 vs. baseline diameter), indicating impairment of renal autoregulatory function. Acute administration of polyethylene glycol superoxide dismutase (PEG‐SOD; 100 units/ml in blood) for 20–30 minutes prior to study restored autoregulatory responses in IR rats (n=6). In PEG‐SOD treated kidneys, reducing perfusion pressure to 65 mmHg increased arteriole diameter to 115 ± 4% of baseline, whereas increasing perfusion pressure to 170 mmHg led to a diameter decrease to 71 ± 6% (P<0.05 vs. IR). These pressure‐mediated responses were indistinguishable from the sham afferent arterioles (P>0.05), suggesting improvement in renal autoregulatory performance. In a similar study, administration of polyethylene glycol catalase (1000 units/ml in blood) also improved afferent arteriole autoregulatory responsiveness in IR rats (n=7). We also found that IR led to significant elevation of mRNA expression of the inflammatory cytokines, monocyte chemoattractant protein‐1 (MCP‐1) and transforming growth factor‐β (TGF‐β), and NADPH oxidase subunit p67 phox in renal microvessels (n=4–7/each group). MCP‐1 and TGF‐β mRNA expression increased 10 fold (10.8 ± 1.6 vs.1.0 ± 0.8, P<0.05) and 3.5 fold (3.5 ± 0.3 vs. 1.0 ± 0.1, P<0.05), respectively, while p67 phox expression was 7 fold higher (7.3 ± 1.5 vs. 1.1 ± 0.3, P<0.05) in renal microvessels of IR rats compared to sham rats. In conclusion, these results suggest that excess ROS generation possibly via elevation of superoxide and/or hydrogen peroxide contribute to impaired renal autoregulation in IR‐AKI rats and are likely associated with activation of MCP‐1 and TGF‐β in renal microvasculature. Support or Funding Information This study was supported by NIH R01 (DK106500) and AHA Grant‐in‐Aid, the Greater Southeast Affiliate (15GRNT25240015) to Guan and by NIH R01 (DK044628) to Inscho. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .