Hyperuricemia (HUA) is a symptom of high uric acid (UA) caused by excessive UA production or decreased excretion. HUA is a metabolic problem that has become increasingly common worldwide, and its association with hypertension has been studied for more than 130 years . UA is the end product of purine metabolism, which is predominantly performed by the proximal tubules . Two main sources of purine in humans have been identified: one is the synthesis of endogenous purine, and the other is the intake of a purine-rich diet [3, 4]. Purines are natural compounds present in all cells of the body and substantially all eatables . If the intake of seafood and meat is too high, high levels of serum uric acid (SUA) may occur, but the total protein consumption is not . SUA is the most plentiful spontaneous antioxidant in human plasma . Its antioxidant properties prevent damage caused by free radicals, reducing the risk of MCI and dementia associated with oxidative stress . Normally, 30% of UA in the human body is excreted from the intestine and bile duct, and 70% is excreted through the kidney [9, 10]. HUA was defined as a UA concentration > 7.0 mg/dl [11–13]. Although SUA seems to be a significant antioxidant in the human body and is thought to protect the human body when present at normal levels, an in-depth analysis of whether UA is adversely active, acting as a pro-oxidant and activator of phlogistic pathways, is needed [14–18]. The body maintains a balance between the production and excretion of UA every day to maintain the normal level of UA. In recent years, the incidence of HUA has increased rapidly [19, 20].
Despite increasing evidence for a direct correlation of HUA with cognitive function, our understanding of the syndrome is limited, and few therapeutic options are available . In recent research, scholars found that HUA exerts a certain effect on cognitive function . We chose to generate a rat model by feeding them special diets. Extensive evidence has shown the validity of the Morris water maze (MWM) as a method for assessing hippocampus-dependent reference memory and spatial guidance , its specificity as an evaluation of place memory, and its relative immunity to motivational differences across a series of experimental therapies that are secondary to the key purpose of the study, such as pharmacological treatment, lesions, and genetic manipulation. Therefore, after the model was successfully established, we administered an MWM test to all rats to assess the effects of HUA on MCI. We measured the blood biochemical parameters of all rats to confirm the successful establishment of the model. Then, we performed a whole transcriptome analysis of rat hippocampal tissues after the modeling cycle. The hippocampus is a component of the limbic system in the brain, and the exact location is between the thalamus and medial temporal lobe. The hippocampus is mainly responsible for the storage, orientation and conversion of long-term memory .
A whole transcriptome analysis aims to assess the sum of all RNA that a particular cell can transcribe in a particular state and involves mRNA and noncoding RNA (ncRNA) . Research on ncRNAs mainly focuses on miRNAs, lncRNAs and circRNAs, with regulatory effects identified based on second-generation sequencing technology. The whole transcriptome sequence is studied, and mRNAs, lncRNAs, circRNAs, and miRNAs are analyzed. Through a pairwise association analysis, ternary association analysis and multivariate association analysis, the research is more systematic, and the changes in transcriptional regulation underlying biological phenomenon are explored in depth.
Previous studies have claimed that UA in human vascular cells and endothelial cells upregulates C-reactive protein (CRP), an inflammation marker [26, 27]. Furthermore, various illnesses caused by HUA are related to activation of the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway . TLRs are important protein molecules involved in nonspecific immunity (innate immunity) and a bridge between nonspecific immunity and specific immunity . Based on accumulating evidence, UA-induced activation of TLR4 damages hippocampus-dependent spatial relation memory in an inflammation-dependent manner and diminish the hippocampal pyramidal neuron dendrite length [29, 30]. An erstwhile study suggested that SUA functions as a mighty inflammatory stimulus that is transported across the blood-brain barrier [23, 31]. A few studies have shown that an increase in UA levels might affect cognitive functioning by inducing cerebrovascular changes [32, 33]. Here, we established a HUA model in which rats were provided with a high-UA diet (HUAD) and were used as the experimental group, while the rats in the control group were provided with normal basic feed as the control group. RNA-seq was used to identify differentially expressed RNAs and methodically analyze the genetic background of HUA-induced MCI. We found that HUA altered gene expression in the hippocampus and modulated a series of signaling pathways to induce encephalopathy.
We construct models to explore the real cause of the effects of HUA on the function of the hippocampus and to identify the specific targets. In summary, in this study, we performed whole-transcriptome sequencing to screen the differentially expressed mRNAs, lncRNAs, miRNAs and circRNAs. Therefore, based on the bioinformatics analysis, mRNA-lncRNA-miRNA networks were established, and then we identified the biological functions of the target genes.