5/6 Nephrectomy Induces Changes in Immune and Inflammatory Gene Expression in the Left Ventricle

Abstract

Chronic kidney disease (CKD) patients have increased cardiovascular risk. We have used 5/6 nephrectomy (5/6 NX) in Sprague Dawley rats to investigate the molecular mediators of cardiac pathology in this condition. Understanding gene expression changes in the heart could yield valuable information about pathology mediators and identify therapeutic targets. The goal of this study was to characterize changes in left ventricle (LV) gene expression following 5/6 NX. Reproducible alterations in LV structure and function were observed in the weeks following 5/6 NX including enhanced function (2 weeks), hypertrophic remodeling (4 and 5 weeks), and dilation with reduced function (7 weeks post). We performed next‐generation sequencing of mRNA extracted from the LV of 5/6 NX and sham rats at these time points (2 pools/group, 2‐3 animals/pool). Genes from our data set with an average fold change of >1.5 (vs. sham) were analyzed using DAVID and Ingenuity Pathway Analysis. Several signaling pathways were enriched with identified genes in a time dependent manner, corresponding with pathological LV changes. However, we found enrichment of altered genes in numerous immune system and inflammatory pathways throughout the study, including pathways related to atherosclerosis, granulocyte and agranulocyte movement, and innate and adaptive immune signaling. This study provides the first gene expression data showing that a reduction in renal mass alone can drive broad immune related gene expression changes in LV tissue. Further, these genes are altered beginning as early as 2 weeks after 5/6 NX, long before cardiac remodeling or dysfunction are observed. Support 13SDG17100095 and 8UL1TR000055.