# The Effect of Nerolidol Renal Dysfunction following Ischemia-Reperfusion Injury in the Rat
## 5 Discussion  
In the current study, we investigated, for the first time, the effect of meridold on renal dysfunction following IRI. We have shown that the administration of this agent prior to and soon after IRI can significantly attenuate IRI-induced alterations in renal functional parameters such as serum creatinine, creatinine clearance and urinary albumin leakage. It also significantly attenuated changes in the gene expression of markers of acute renal injury; proinflammatory, profibrotic and proapoptotic cytokines; and oxidative stress markers. Our data also show a significant improvement in the tissue level of oxidative stress markers and in histopathological changes. IRI-induced renal damage is caused by both ischemia and reperfusion, leading to hypoxia and excessive production of reactive oxygen species, respectively. This damage is also associated with an inflammatory response characterized by increased production  
Figure 8: Histological features in all the experimental groups. (**A**,**B**) The kidneys in G-Sham showed normal architecture and histology. (**C**,**D**) Histological features in the G-IRI with diffuse acute tubular necrosis (thin arrow) and intratabular necrotic material and secretions (arrowhead). (**E**,**F**) Histological features in G-IRI/NR with mild acute tubular necrosis and tubular dilation (thin arrow) and intratabular secretion (arrowhead). of several cytokines such as proinflammatory and profibrotic cytokines, including TNF-\(\alpha\), TGF-\(\beta\)1 and PAI [21; 22; 23; 24; 25; 26]. In the current study, meridold was shown to have a significant antioxidant effect, as demonstrated by its effects on the gene expression of some oxidative stress enzymes, namely glutathione peroxidase and glutathione-disulfide reductase, as well as on the tissue concentration of glutathione and malondialdehydedehyde. The antioxidant and free radical scavenging properties of meridold have been demonstrated in other models, such as memory impairment caused by Trypanosoma evansi in mice [27], thioacetamide-induced oxidative damage in heart and kidney tissue [18] and isoproterenol-induced myocardial damage [13]. The contradictory downregulation in the gene expression of the oxidative enzymes and in their tissue concentration observed in this study has been previously demonstrated by other studies in IRI [28; 29] and other conditions [30; 31] in which oxidative stress plays a major role in the pathophysiology of the disease process. This downregulation of mRNA has been attributed to the higher turnover of these enzymes at different levels [28]. Regardless of the exact reason, meridold led to a significant attenuation of this process in renal IRI. In addition to its antioxidant properties, the current data demonstrate anti-inflammatory and antifibrotic properties of meridold, as shown by the attenuation of the IRI-induced rise in the gene expression of TNF-\(\alpha\), TGF-\(\beta\)1, PAI, IL-1 \(\beta\) and IL-6. TNF-\(\alpha\) is a proinflammatory cytokine that is produced by several tissues including renal cells [32]. TGF-\(\beta\) is a profibrotic cytokine that stimulates renal cells to produce extracellular matrix proteins, leading to long-term glomerulosclerosis and tubulointerstitial fibrosis [26; 33]. PAI-1 is also a profibrotic cytokine, as it is considered one of the major inhibitors of fibrinolysis [34; 35]. All these cytokines are upregulated in the majority of renal diseases [23; 24; 26], and the effect of meridold on these cytokines in renal IRI appears to be similar to its effect in other conditions [17]. The anti-inflammatory and antioxidant properties of meridold observed in the current study led to an amelioration of IRI-associated renal functional damage, as shown by the significant attenuation in serum creatinine and creatinine clearance. The improvement in urinary albumin leakage in addition to these parameters indicates that meridold not only affects glomerular function but also renal tubular function.