STX-0119, a novel STAT3 dimerization inhibitor, prevents fibrotic gene expression in a mouse model of kidney fibrosis by regulating Cxcr4 and Ccr1 expression.

Abstract

Kidney fibrosis is a histological hallmark of chronic kidney disease (CKD) and is believed to be involved in the progression of CKD. Therefore, inhibition of kidney fibrosis is a potential strategy for slowing CKD progression. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated by interleukin-6 and is reported to be involved in fibrosis. Previously, S3I-201, an inhibitor of STAT3 phosphorylation, was shown to inhibit renal fibrosis in a mouse model, but its mechanism was not clarified completely. In this study, we investigated whether STX-0119, a new inhibitor of STAT3 dimerization, suppressed kidney fibrotic gene expression using a mouse model of kidney fibrosis and examined the underlying mechanisms. Kidney fibrosis was induced by unilateral ureteral obstruction (UUO), which was accompanied by upregulation of STAT3 target genes. STX-0119 administration suppressed the expression of fibrotic genes in UUO kidneys without affecting STAT3 phosphorylation. STX-0119 decreased Cxcr4 mRNA in cultured rat kidney fibroblasts and Ccr1 mRNA in blood cells from UUO mice, both of which are reported to be involved in the progression of kidney fibrosis. These results suggest that STX-0119 inhibits fibrotic gene expression in kidney by suppressing Cxcr4 and Ccr1 expression. This is the first report to indicate a part of the mechanism of the antifibrotic effects of a STAT3 inhibitor and suggests that STX-0119 may be a lead compound for the treatment of kidney fibrosis.

• Authors: Kouki Makitani, Naohisa Ogo, Akira Asai
• Journal: Physiological reports (Physiol Rep) Vol. 8 Issue 20 Pg. e14627 (10 2020) ISSN: 2051-817X [Electronic] United States
• PMID: 33112058 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Chemical References

• CXCR4 protein, mouse
• Ccr1 protein, mouse
• Oxadiazoles
• Quinolines
• Receptors, CCR1
• Receptors, CXCR4
• STAT3 Transcription Factor
• STX-0119

Topics

• Animals
• Fibroblasts (drug effects, metabolism)
• Fibrosis
• Kidney (drug effects, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Oxadiazoles (pharmacology)
• Quinolines (pharmacology)
• RAW 264.7 Cells
• Rats
• Receptors, CCR1 (genetics, metabolism)
• Receptors, CXCR4 (genetics, metabolism)
• Renal Insufficiency, Chronic (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)