The present study demonstrated that, according to the selected biochemical and histological parameters of renal dysfunction, ATO treatment 30 min after ischemia mitigated the course of ischemic ARF in rats. This observation was supported by several key findings. ATO treatment 30 min after ischemia significantly ameliorated post-ischemic acute tubular necrosis and considerably limited the structural damage after ischemia. Histologically, ATO treatment reduced the damage to proximal tubules in the renal cortex. Untreated animals demonstrated typical changes: loss of the brush border, destruction of epithelial cells, “naked” basement membranes, and tubular obstruction. The major changes in tubules (loss of nuclei and appearance of tubular debris and casts) were remarkable. Moreover, ATO treatment reduced the serum levels of creatinine and increased the Ccr, which are indicators of impaired glomerular function. As mentioned above, despite intervention being after ischemic injury, ARF could be ameliorated with statin treatment.
There are several possible mechanisms for the protective effects of ATO. Recent studies have shown that ROS, certain inflammatory mediators (e.g., ICAM-1, MCP-1 [7, 8]), and infiltration of inflammatory cells are related to renal ischemia–reperfusion injury . During ischemia–reperfusion injury, reperfused tissues generate a great deal of ROS through activation of xanthine oxidase and NADPH oxidase. ROS not only elicit injury to reperfused tissue directly, they also amplify the effect of injury of ROS through peroxidation (oxidative stress). This view is consistent with the notion that oxidative stress increases in critically ill patients with acute kidney injury (AKI) .
AOPPs are derived from oxidation-modified albumin (its aggregates or fragments), and are recognized as markers of oxidative damage to proteins, the intensity of oxidative stress, and inflammation . Accumulation of AOPPs is probably via a redox-sensitive inflammatory pathway that causes deterioration in renal dysfunction  and it is also a prognostic biomarker for recovery from AKI after coronary artery bypass grafting . Furthermore, ROS also cause renal-cell injury by lipid peroxidation, which results in increased membrane permeability in cells, mitochondria, and lysosomes. MDA is one of several low-molecular-weight end products formed via the decomposition of certain primary and secondary lipid peroxidation products . MDA is a reliable estimator of lipid peroxidation .
We found that ischemia–reperfusion injury led to an increase in levels of AOPP and MDA that were decreased by ATO treatment. These results suggest that the protection afforded by ATO may be mediated by reducing oxidative stress, particularly by decreasing the production of oxygen free radicals and lipid peroxidation in cells.
Inflammation is another important factor causing ischemia–reperfusion renal damage. Infiltration of inflammatory cells in ischemia–reperfusion injury is accompanied by significant upregulation of expression of adhesion molecules [7, 8]. Upregulation of expression of ICAM-1 and MCP-1 in glomeruli, renal tubules, and the peritubular interstitium was also prevented by ATO treatment. Our results showed that even administration of ATO after ischemic ARF elicited anti-inflammatory actions.
The most prominent injury to renal proximal tubular cells is likely to occur during the first 2–4 h of the reperfusion period. Sixty minutes of ischemia does not increase MDA levels, whereas 15 min of reperfusion results in a large increase in kidney lipid peroxidation and aggravates cell injury [14, 15]. Hence, ATO administration 30 min before reperfusion can protect the kidney.
In other studies, statin intervention has been several days before ischemia–reperfusion injury [26, 27] but, in the present study, drug intervention was after renal ischemia. AKI is an unpredictable event, so the present study has more clinical relevance compared with previous studies. Haylor et al. reported that even if ATO was administered after clamping the renal hilus but before kidney reperfusion, renal ischemia–reperfusion injury can be improved because of direct inhibition of activated caspase-3 in rats . Our results are consistent with the findings of that study but we studied whether ATO treatment after renal ischemia also had anti-inflammatory and anti-oxidative stress effects. In their study, ATO did not change Scr levels but in the present study Scr levels were decreased and Ccr levels increased in ATO groups. This finding may be because we determined Scr levels 24 h after reperfusion, whereas in their study it was at 4 h. Scr levels and the Ccr are the most important indices of renal function. Taken together, the renal protection afforded by ATO is not obvious 4 h after reperfusion but its effects continue for ≥4 h. The present study showed that renal function could obviously recover in 24 h even if ATO was given after ischemia.