The Monocyte Chemotactic Protein-1 Gene May Contribute to Hypertension in Dahl Salt-Sensitive Rats

Abstract

In a previous study, we performed a genome-wide quantitative trait loci (QTLs) analysis for blood pressure using F2 rats derived from Dahl salt-sensitive (DS) and Lewis (LEW) rats and identified two QTLs that influenced blood pressure levels. Although we determined that one of the causative genes in the chromosome (Ch) 1 region seemed to be Klk1, we did not perform detailed analyses on the Ch10 QTL region. The purpose of the present study was to identify candidate genes that influence blood pressure in the Ch10 QTL region. Using microarray analysis, we compiled a list of the genes that are differentially expressed between the two strains and that were localized to the Ch10 QTL region. Subsequent reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis identified that, while the expression levels of Ccl2 mRNA were not different between the kidneys of DS and LEW rats fed a normal diet, those in DS were 10-fold higher than those in LEW under a high-salt diet. Although the promoter reporter assay failed to identify causative nucleotide changes that led to the differential expression, monocyte chemotactic protein-1 (MCP-1) release from isolated monocytes were significantly higher in DS than in LEW. Intriguingly, this Ch10 QTL for blood pressure was also a possible QTL for urinary albumin excretion. Since Ccl2 is well known to be involved in various types of renal injury, it is likely that a higher expression of Ccl2 might aggravate macrophage infiltration, which in turn could aggravate tubulointerstitial injury, and thereby accelerate salt-sensitive hypertension. Thus, Ccl2 appears to be a interesting candidate gene for salt-sensitive hypertension in DS.