Arid5a/IL-6/PAI-1 Signaling Is Involved in the Pathogenesis of Lipopolysaccharide-Induced Kidney Injury

• Published in: Biological & pharmaceutical bulletin Vol. 46; no. 12; pp. 1753 - 1760
• Main Authors: Tanaka, Koki, Harada, Hiroki, Kamuro, Hiroyasu, Sakai, Hibiki, Yamamoto, Ayaha, Tomimatsu, Masashi, Ikeda, Akari, Chosokabe, Renya, Tanaka, Shota, Okada, Yoshiaki, Fujio, Yasushi, Obana, Masanori
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01-12-2023; Japan Science and Technology Agency
• Subjects: adenine–thymine-rich interactive domain-containing protein 5a (Arid5a); Animal models; Cell culture; Creatinine; endothelial cell; Endothelial cells; Enzyme-linked immunosorbent assay; Gene expression; Inflammation; interleukin (IL)-6; Interleukin 6; Kidney diseases; kidney injury; Kidneys; lipopolysaccharide (LPS); Lipopolysaccharides; Pathogenesis; plasminogen activator inhibitor-1 (PAI-1); Plasminogen activator inhibitors; Sepsis; Thymine; Umbilical vein
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b23-00482

A systemic inflammatory response leads to widespread organ dysfunction, such as kidney dysfunction. Plasminogen activator inhibitor-1 (PAI-1) is involved in the pathogenesis of inflammatory kidney injury; however, the regulatory mechanism of PAI-1 in injured kidneys remains unclear. PAI-1 is induced by interleukin (IL)-6 in patients with sepsis. In addition, the stabilization of IL-6 is regulated by the adenine–thymine-rich interactive domain-containing protein 5a (Arid5a). Therefore, the aim of the present study was to examine the involvement of Arid5a/IL-6/PAI-1 signaling in lipopolysaccharide (LPS)-induced inflammatory kidney injury. LPS treatment to C57BL/6J mice upregulated Pai-1 mRNA in the kidneys. Enzyme-linked immunosorbent assay (ELISA) revealed that PAI-1 expression was induced in the culture supernatants of LPS-treated human umbilical vein endothelial cells, but not in those of LPS-treated human kidney 2 (HK-2) cells, a tubular cell line. Combined with single-cell analysis, endothelial cells were found to be responsible for PAI-1 elevation in LPS-treated kidneys. Administration of TM5441, a PAI-1 inhibitor, reduced the urinary albumin/creatinine ratio, concomitant with downregulation of Il-6 and Arid5a mRNA expressions. IL-6 treatment in LPS model mice further upregulated Pai-1 mRNA expression compared with LPS alone, accompanied by renal impairment. Furthermore, the expression of Il-6 and Pai-1 mRNA was lower in Arid5a knockout mice than in wild-type mice after LPS treatment. Taken together, the vicious cycle of Arid5a/IL-6/PAI-1 signaling is involved in LPS-induced kidney injury.