Evaluation of differentially expressed genes and their roles in pathophysiological changes caused by uric acid accumulation

In primates, including Homo sapiens, the final metabolite of purine catabolism is uric acid, which is excreted via the kidneys and gastrointestinal tract. However, in other placental mammals, this pathway is continued. Through reactions catalyzed by the enzymes urate oxidase (uricase), HIU hydrolase (HIUase) and OHCU decarboxylase, uric acid is degraded to (S)-allantoin. Furthermore, in certain organisms, such as frogs and teleosts, (S)-allantoin is hydrolyzed by allantoinase and allantoicase, producing (S)-ureidoglycolate and urea. In H. sapiens, studies with the enzymes of the purine catabolic pathway have shown that the occurrence of mutations in the uricase gene leads to the inactivation of the genes of other enzymes of the pathway. The lack of expression of these enzymes lead to negative consequences in cases of uric acid accumulation. In addition to its association with gout, hyperuricemia is considered a risk factor for the development and/or progression of cardiovascular disease and diabetes, and a predictor of the severity of preeclampsia. Nevertheless, a significant number of drugs widely used in the population, including aspirin, a non-steroidal anti-inflammatory drug (NSAID) used in low doses for secondary prevention of ischemic events, can increase uric acid levels, even at therapeutic doses. Despite the absence of the translated proteins in H. sapiens, transcripts of uricase (UOX), HIUase (URAHP), OHCU decarboxylase (URAD), and allantoicase (ALLC), and URAHP are expressed as long non-coding RNAs (lncRNAs) and pseudogenes. These macromolecules have different regulatory functions and can alter gene expression through various mechanisms. LncRNA can also be translated by alternative translation pathways, leading to the formation of small peptides with important regulatory functions. Considering the presence of these transcripts, we hypothesized that the transcriptional regulation of the genomic regions associated could be involved in the pathogenesis of diseases with hyperuricemia. To test this hypothesis, we searched the Sequence Read Archive (SRA) for case-control studies involving pre-eclampsia, hypertension, or aspirin to obtain raw RNA sequencing (RNA-seq) data. From these data, transcript quantification was performed using Salmon software, the quantification results were imported into R using the Tximeta package, and differential expression analysis was performed using the DESeq2 and the swish function of fishpond package. Thus, it became possible to evaluate the differential expression in the gene regions of uricase (UOX), HIUase (URAHP), OHCU decarboxylase (URAD) and allantoicase (ALLC), to better understand the mechanisms of biological action of these transcripts in hyperuricemia.
This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).