Abstract
Profiling of temporal changes of gene expression in the same kidney over the course of renal disease progression is challenging because repeat renal biopsies are rarely indicated in clinical practice. Here, we profiled the temporal change in renal transcriptome of HIV-1 transgenic mice (Tg26), an animal model for human HIV-associated nephropathy (HIVAN), and their littermates at three different time points (4, 8, and 12 weeks of age) representing early, middle, and late stages of renal disease by serial kidney biopsy. We analyzed both static levels of gene expression at three stages of disease and dynamic changes in gene expression between different stages. Analysis of static and dynamic changes in gene expression revealed that up-regulated genes at the early and middle stages are mostly involved in immune response and inflammation, whereas down-regulated genes mostly related to fatty acid and retinoid metabolisms. We validated the expression of a selected panel of genes that are up-regulated at the early stage (CCL2, CCL5, CXCL11, Ubd, Anxa1, and Spon1) by real-time PCR. Among these up-regulated genes, Spon1, which is a previously identified candidate gene for hypertension, was found to be up-regulated in kidney of human with diabetic nephropathy. Immunostaining of human biopsy samples demonstrated that protein expression of Spon1 was also markedly increased in kidneys of patients with both early and late HIVAN and diabetic nephropathy. Our studies suggest that analysis of both static and dynamic changes of gene expression profiles in disease progression avails another layer of information that could be utilized to gain a more comprehensive understanding of disease progression and identify potential biomarkers and drug targets.
Highlights
Most patients with chronic kidney disease (CKD) progress to end stage renal failure (ESRD) despite medical intervention [1] [2]
Periodic acid-Schiff (PAS)-stained kidney sections from Tg26 mice and the littermates were graded by a renal pathologist blinded to genotypes as described in the method
Gene expression profiles in the kidney cortices of Tg26 and their control littermates at these three time points were assessed by next-generation sequencing of mRNA extracted from the kidney cortex
Summary
Most patients with chronic kidney disease (CKD) progress to end stage renal failure (ESRD) despite medical intervention [1] [2]. The transcriptiomic approach is one of the most promising and advanced methods for identifying biomarkers and studying disease pathogenesis. This approach is not without its limitations. It is impossible to obtain a temporal change of gene profiles in patients over the entire course of the disease. Due to these factors, the clinical utility of current human transcriptomic data is limited. We examined the temporal profile of gene expression over the course of disease progression by serial sampling of the kidney
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