Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Thromboxane A2 Receptor Antagonist (ONO-8809) Attenuates the Renal Disorders Caused by Salt-Overload in Stroke-Prone Spontaneously Hypertensive Rats

Version 1 : Received: 17 January 2021 / Approved: 18 January 2021 / Online: 18 January 2021 (11:32:11 CET)

How to cite: Nagatani, Y.; Higashino, T.; Kinoshita, K.; Higashino, H. Thromboxane A2 Receptor Antagonist (ONO-8809) Attenuates the Renal Disorders Caused by Salt-Overload in Stroke-Prone Spontaneously Hypertensive Rats. Preprints 2021, 2021010319 (doi: 10.20944/preprints202101.0319.v1). Nagatani, Y.; Higashino, T.; Kinoshita, K.; Higashino, H. Thromboxane A2 Receptor Antagonist (ONO-8809) Attenuates the Renal Disorders Caused by Salt-Overload in Stroke-Prone Spontaneously Hypertensive Rats. Preprints 2021, 2021010319 (doi: 10.20944/preprints202101.0319.v1).

Abstract

Background. Epidemiological and clinical studies demonstrated that excessive salt intake causes severe hypertension and exacerbated organ derangement such as chronic kidney disease (CKD). In this study, we focused on evaluating histological and gene-expression findings in the kidney using stroke-prone spontaneously hypertensive rats (SHRSP) with high-salt intake and thromboxane A2/ prostaglandin H2 receptor (TPR) blocker ONO-8809. Methods. SHRSP aged 6 weeks were divided into three groups eating normal chow containing 0.4% NaCl, 2.0%NaCl, or 2.0%NaCl +ONO-8809 (0.6mg/kg p.o. daily). Histological analyses with immunohistochemistry and a gene-expression assay with a DNA kidney microarray were performed after 8 weeks. Results. The following changes were observed with high-salt intake. Glomerular sclerotic changes were remarkably observed in the juxtaglomerular cortex areas. ED1, MCP-1, nitrotyrosine, and HIF-1α staining areas were increased in the glomeruli and interstitial portion. Tbxa2r which encodes TPR, Prcp, and Car7 were significantly underexpressed in the kidney. The plasma 8-isoprostane level was significantly elevated, and was attenuated with ONO-8809 treatment. Conclusion. TXA2 and oxidative stresses exaggerated renal dysfunction in salt-loading SHRSP, and ONO-8809 as a TPR blocker suppressed these changes. Therefore, ONO-8809 is a candidate drug to prevent CKD for hypertensive patients associated with high-salt intake.

Keywords

thromboxane A2 and prostaglandin H2 receptor (TPR) antagonist; ONO-8809; renal disorders; salt-overload; stroke-prone spontaneously hypertensive rat (SHRSP); hypertension; oxidative stress

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