Thromboxane A(2) receptor antagonist (ONO‐8809) attenuates renal disorders caused by salt overload in stroke‐prone spontaneously hypertensive rats

Epidemiological and clinical studies have demonstrated that excessive salt intake causes severe hypertension and exacerbates organ derangement, such as in chronic kidney disease (CKD). In this study, we focused on evaluating the histological and gene expression effects in the kidneys of stroke‐prone spontaneously hypertensive rats (SHRSP) with a high salt intake and the thromboxane A(2)/ prostaglandin H(2) receptor (TPR) blocker ONO‐8809. Six‐week‐old SHRSPs were divided into three groups and were fed normal chow containing 0.4% NaCl, 2.0%NaCl or 2.0%NaCl + ONO‐8809 (0.6 mg/kg p.o. daily). Histological analyses with immunohistochemistry and a gene expression assay with a DNA kidney microarray were performed after 8 weeks. The following changes were observed in SHRSPs with the high salt intake. Glomerular sclerotic changes were remarkably observed in the juxtamedullary cortex areas. The ED1, monocyte chemoattractant protein‐1 (MCP‐1), nitrotyrosine and hypoxia inducible factor 1α (HIF‐1α) staining areas were increased in the glomeruli and interstitial portion of the kidneys. The genes Tbxa2r (that encodes TPR), Prcp and Car7 were significantly underexpressed in the kidneys. The plasma 8‐isoprostane level was significantly elevated and was attenuated with the ONO‐8809 treatment. Thromboxane A(2) (TXA(2)) and oxidative stress exaggerated renal dysfunction in the salt‐loaded SHRSPs, and ONO‐8809 as a TPR blocker suppressed these changes. Therefore, ONO‐8809 is a candidate drug to prevent CKD in hypertensive patients when CKD is associated with a high salt intake.