Identification of mechanistic chronic kidney disease biomarkers by comprehensive bulk RNA-seq transcriptomics and SWATH proteomics of the rat sub-total nephrectomy model of kidney fibrosis [RNA-Seq_1]

The rat sub-total nephrectomy (SNx) is a functional model of chronic kidney disease (CKD), where the main pathological driver is glomerular hypertension. Comprehensive transcriptomics and proteomics analyses on the rat SNx model were performed to identify biomarkers in plasma or urine that correlate with kidney disease and functional kidney loss. Kidneys were subjected to collagen I and III staining for fibrosis scoring, SWATH proteomics and bulk RNA-sequencing transcriptomics (RNA-seq), with SWATH also performed on plasma and urine. Differential expression analysis demonstrated significant dysregulation of genes and proteins involved in fibrosis, metabolism, and immune response in the SNx rats compared to controls. Gene ontology analysis of the intersecting genes and proteins from both studies demonstrated common biology between animal cohorts that reached the predefined kidney disease thresholds (serum creatinine >2-fold or proteinuria >3-fold increase over sham-operated). Thirteen significantly differential molecules were detected with consistent directional changes in both transcriptomics and proteomics datasets. These molecules were detected independently in kidney (both RNA and protein) and urine (protein only), but not in plasma. The bioinformatics analysis enabled the identification of mechanistic CKD biomarkers including lumican and collagen alpha-1(III) chain, whose co-expression has previously been both implicated in fibrosis and detected in urine in CKD patients. Overall design: Case Control