Abstract
Renal fibrosis is the pathological repair reaction of the kidney to chronic injury, which is an important process of chronic kidney disease (CKD) progressing to end-stage renal failure. Nephrolithiasis is one of the most common renal diseases, with waist and abdomen pain, hematuria, urinary tract infection, and other clinical symptoms, which can increase the risk of renal fibrosis. Oxalate crystal-induced kidney injury is an early stage of nephrolithiasis; it is of great significance to explore the mechanism for the prevention and treatment of nephrolithiasis. A rodent model of calcium oxalate (CaOx) crystal-induced kidney injury was used in the present study, and a network analysis method combining proteomics and metabolomics was conducted to reveal the mechanism of crystal kidney injury and to provide potential targets for the intervention of nephrolithiasis. Using the metabolomics method based on the UHPLC-Q/TOF-MS platform and the iTRAQ quantitative proteomics method, we screened a total of 244 metabolites and 886 proteins from the kidney tissues that had significant changes in the Crystal group compared with that in the Control group. Then, the ingenuity pathway analysis (IPA) was applied to construct a protein-to-metabolic regulatory network by correlating and integrating differential metabolites and proteins. The results showed that CaOx crystals could induce inflammatory reactions and oxidative stress through Akt, ERK1/2, and P38 MAPK pathways and affect amino acid metabolism and fatty acid β-oxidation to result in kidney injury, thus providing an important direction for the early prevention and treatment of nephrolithiasis.
Highlights
Nephrolithiasis is one of the most common diseases in urology, with waist and abdomen pain, hematuria, urinary tract infection, and other clinical symptoms, and it increases the risk of chronic kidney disease (CKD), renal fibrosis, coronary heart disease, and stroke [1–3]
The dataset containing ID, fold change values, and p-values of differentially expressed proteins and metabolites was uploaded to ingenuity pathway analysis (IPA) for core analysis, in which the canonical pathways, diseases and functions, upstream regulator analysis, toxicity analysis, and network analysis associated with calcium oxalate (CaOx) crystal-induced kidney injury could be carried out
The representative total ion chromatograms (TICs) of tissue samples and quality control (QC) samples acquired using the abovementioned UHPLC-Q/TOF-m/z values (MS) methods are shown in Supplementary Figure 2
Summary
Nephrolithiasis is one of the most common diseases in urology, with waist and abdomen pain, hematuria, urinary tract infection, and other clinical symptoms, and it increases the risk of chronic kidney disease (CKD), renal fibrosis, coronary heart disease, and stroke [1–3]. Renal fibrosis is the pathological repair reaction of the kidney to chronic injury, which is an important process of CKD progressing to end-stage renal failure [4]. Proteomics and Metabolomics Reveal Nephrolithiasis many years, making it difficult to identify disease progression before the kidney function is severely impaired or even the failure occurs. With rapid development in high-throughput technologies, proteomics and metabolomics have been widely used to study the mechanisms of kidney diseases [5–7], such as CKD, acute kidney injury, and diabetic kidney disease. A combined network analysis of proteomics and metabolomics is an effective tool for exploring the potential mechanism of gene phenotype [8]. Research on nephrolithiasis disease mainly focuses on the mechanism of stone formation [10, 11], early diagnosis technology [12, 13], treatment strategy [14, 15], etc. We focused on an integrated analysis strategy of proteomics and metabolomics, rather than single proteomics [16] or metabolomics [17], to analyze the internal changes of mice with kidney stones in many aspects, so as to overcome the limitations of single omics and aim to further reveal the changes of metabolic regulatory networks in mice with kidney stones
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