# The Effect of Nerolidol on Renal Dysfunction following Bilateral Ureteral Obstruction
## 4 Discussion  
Obstructiveropathy is a common cause of acute kidney injury characterized by the hindrance of normal urine flow through the urinary tract, resulting from various structural and functional etiologies [22; 23; 24]. It affects all age groups and can lead to detrimental consequences if left untreated. Our results suggested that the administration of nerolidol can ameliorate the alterations in renal functions, the gene expression levels of key kidney injury markers, pro-inflammatory and pro-apoptotic cytokines, oxidative stress markers, and kidney histology induced by BUO injury Figure 6.  
In the current study, we have shown that nerolidol has anti-inflammatory effects on the kidney following BUO. It has mitigated alterations in TNF-\(\alpha\), IL-1\(\beta\), IL-6, and PAI-1. TNF-\(\alpha\) is a versatile pro-inflammatory cytokine that is produced by macrophages and monocytes during acute inflammation [25]. It is a versatile cytokine that is essential in various cellular processes, including cell survival, proliferation, differentiation, and cell death [26]. Its primary role is to mount and regulate the immune response by triggering the production of other important pro-inflammatory cytokines, including IL-1\(\beta\) and IL-6 [27; 28]. However, the overexpression of TNF-\(\alpha\) due to severe injury could lead to detrimental consequences. Our gene expression analysis revealed that nerolidol significantly attenuated the BUO-induced excessive upregulation in the gene expression of TNF-\(\alpha\) in G-BUO/NERO. The exact mechanism for this attenuation is difficult to ascertain from the current study, but could possibly be attributed to the inhibition of TLR4 stimulation by nerolidol, which has been previously demonstrated in other organs [29]. The ability of nerolidol to target the TLR4/NF-\(\kappa\)B signaling cascade might interfere with the translocation of phosphorylated nuclear factor-\(\kappa\)B (p-NF-\(\kappa\)B), an important agent which triggers the synthesis of pro-inflammatory cytokines including TNF-\(\alpha\)[15; 30]. Regardless of the exact mechanism of the effect of nerolidol on TNF-\(\alpha\) changes, the findings of this study are consistent with the findings reported in other models of acute kidney injury, such as lipopolysaccharide- and ischemia-reperfusion-induced acute kidney injury [15; 17]. Nerolidol has also attenuated BUO-induced upregulation in IL-6 and IL-1\(\beta\). The former is a major pro-inflammatory cytokine that plays a key role in the recruitment and interstitial infiltration of neutrophils, thereby exacerbating renal injury. IL-1\(\beta\) is also a key mediator of inflammation that typically spikes during acute renal injury and causes systemic inflammation by activating all types of leukocytes via its receptor, IL-1R [31]. The downregulation in the gene expression of both IL-6 and IL-1\(\beta\) could be due to the inhibition of TNF-\(\alpha\) gene expression, as TNF-\(\alpha\) is required to trigger the synthesis and release of these cytokines [27; 28]. These findings are consistent with previous reports on the effect of nerolidol in other injury models [15; 17; 32] and indicate that nerolidol exhibits potent anti-inflammatory properties. Tissue hypoxia is among the pathological consequences of ureteral obstruction [33]. These stress stimuli cause kidney cells to generate and release reactive oxygen species, which in turn exacerbates the renal injury. In the current study, we measured the gene expression level of two important oxidative stress markers, GPx-1 and GSR. The latter,  
Figure 6: Summary of the effects of nerolidol on bilateral ureteral obstruction. which accounts for 96% of all kidney GPx activity [34], exerts its antioxidant effects by enzymatically reducing hydrogen peroxide to water and oxidizing reduced glutathione (GSH) to glutathione disulfide [35]. In contrast, GSR reduces oxidized glutathione disulfide to the sulfhydryl group forming glutathione (GSH), which plays a pivotal role in the cellular antioxidant defense system [36].