This study demonstrated the protective effects of FA against IVR-induced nephrotoxicity. IVR can be taken into the body by oral, subcutaneous or intramuscular routes and can reach the blood and organs such as liver and kidney for metabolism. Although it has been established as a safe and non-toxic drug for mammals it probably has some effects on the oxidative stress system of mammals, considering that it is a xenobiotic for the body. Since the xenobiotic is unknown to the host, it can be expected to cause adverse effects such as toxicity, allergic response, and cancer
17. Moreover, IVR induced oxidative stress in the tissue of North African catfish
24. Common adverse effects of IVR including headache, pruritus, myalgia, cough, dyspnea, nausea, vomiting, diarrhea, blurred vision, postural hypotension, and confusion have been reported in clinical studies. It can also cause nephropathy, psychiatric disorders, liver disorders and multiple organ dysfunction syndrome
25. In the present study, the properties of FA including antiinflammatory effects, reducing interleukin levels and antioxidant effects
26 were invastigated to reduce the nephrotoxic effects of IVR.
Tawfeek et al.3 also reported nephrotoxic effects of IVR on the kidneys, which were similar to our current study. Abdellatefe et al.27 reported that IVR caused hepatorenal toxicity and significantly increased renal biomarkers such as urea and creatinine compared to the control group.
Urea, when quantified in blood, is usually referred to as blood urea nitrogen (BUN) and is a product of protein metabolism. BUN is considered a non-protein nitrogenous (NPN) waste product. Amino acids obtained from protein breakdown undergo deamination to produce ammonia. Ammonia is then converted to urea by liver enzymes. Therefore, urea concentration depends on protein intake, the body's ability to catabolize protein, and adequate urea excretion by the renal system. Urea accounts for the majority (up to 80–90%) of NPN excreted by the body. The body's dependence on the renal system to excrete urea makes it a useful analyte for assessing renal function. Creatinine, also an NPN waste product, is produced from the breakdown of creatine and phosphocreatine and can also be used as an indicator of renal function28. The effect of IVR was investigated biochemically and the results showed an increase in serum renal function markers as presented in Figure 1. Serum urea and creatinine levels high with IVR administration compared to the control group. Consumption of FA in parallel with IVR in rats protected against this deterioration. These findings also emphasized the effect of oral FA in improving metabolism and renal function. These results were consistent with that IVR + FA treated rats showed a significant low in serum urea, supporting the effect of FA as a scavenger of free radicals. Furthermore, some studies reported that rats treated with IVR for 15 days developed a significant high in urea and creatinine levels compared to the untreated group, thus confirming the low in renal glomerular filtration29. High serum urea and creatinine levels as a result of IVR-induced kidney injury in the present study support these observations in previous studies.
Oxidative stress driven by high ROS contributes to the pathogenesis of numerous diseases by causing cellular damage, vascular permeability, tissue necrosis, and lipid peroxidation30. High levels of MDA, a marker of lipid peroxidation, indicate high oxidative stress, while enzymatic antioxidants such as SOD, CAT, and GPx act as essential defense mechanisms by reducing ROS and detoxifying harmful compounds 31. Non-enzymatic antioxidants such as GSH further help neutralize oxidative damage32. Strong antioxidant defenses protect tissues from toxic effects by scavenging free radicals33. While IVR reduces SOD, CAT and GPx activities and non-enzymatic GSH levels34, It was observed that it high MDA levels. FA given with IVR brought these levels closer to the levels of the control group Figure 2.
Xu et al.35 reported the protective effect of therapeutic application with FA on the kidneys, which is consistent with our present study. Also, Jing and Chen36 reported the protective effect of FA against kidney damage in their study on mice.
Proinflammatory cytokines and activation of the systemic inflammatory response are also involved in IVR-induced kidney injury. Inflammatory mediators such as TNF-α, IL-17A and NF-κB play an important role in the pathogenesis of IVR nephrotoxicity 37. These cytokines activate inflammatory cells (neutrophils, macrophages, monocytes, platelets, mastocytes), which emit large amounts of toxic ROS and lead to cellular damage through a variety of mechanisms, including peroxidation of membrane lipids and oxidative damage to DNA and proteins38. In addition, it has been reported that TNF-α transcription is regulated by NF-κB. NF-κB-associated mediators, such as some cytokines and chemokines, play an important role in the promotion of various inflammatory diseases in many organs39. It is also known that DNA damage caused by anticancer therapy activates NF-κB. Therefore, inhibition of NF-κB may be beneficial in reducing kidney damage. Therefore, inhibition of NF-κB may increase sensitivity to apoptosis caused by both chemotherapy drugs and radiation. This study showed that as a result of renal toxicity of IVR, pro-inflammatory cytokines TNF-α, IL-17A and NF-κB levels high compared to the control group Figure 3. In addition, IVR application higher KIM-1 compared to the control group, while AQP-2 lower compared to the control group. FA treatment had the opposite effect when compared to the IVR group Figure 5. Moreover, the nephroprotective effect of FA can be explained by its ability to inhibit the signaling pathway that causes excessive higher in markers such as TNF-α, IL-17A and NF- κB40.
Apoptosis plays an important role in the development and maintenance of homeostasis in most multicellular organisms41. Caspase is known as a group of cysteine proteases and is the main agent of apoptotic cell death. In general, Caspase-3 stands out among caspases42. This is because it is the primary agent that is activated by various death signals and the degradation of important cellular proteins. IVR causes apoptosis through purine and pyrimidine inhibition, leading to DNA defects. Caspase-dependent apoptotic signaling plays an important role in IVR-induced apoptotic damage43. Similarly, another study observed higher apoptosis in kidney tissue after IVR administration. In our study, we used Liu et al.44 In parallel with the results of the study, we found an higher in the expression of Caspase-3 and Bax in rats that received a single dose of IVR, while Bcl-2 expression was lower. In the FA + IVR application, we obtained the opposite results Figure 4. Thus, we observed that IVR induced apoptosis.
In the study of Almawla and Al-baggou45, it was stated that IVR increased proapoptotic biomarkers compared to the control group. In the current study, proapoptotic biomarkers were found to be significantly higher in IVR application compared to the control group.
As a results FA supplementation alleviated IVR-induced renal dysfunctions and reduced oxidative stress. FA suppressed inflammation, oxidative stress and apoptosis associated with IVR toxicity and was therefore beneficial in reducing nephrotoxicity complications.
)
)
)
)
)
)
