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

  • Biol Pharm Bull. 2023;46(12):1753-1760. doi: 10.1248/bpb.b23-00482.
Koki Tanaka  1 ,  Hiroki Harada  1 ,  Hiroyasu Kamuro  1 ,  Hibiki Sakai  1 ,  Ayaha Yamamoto  1 ,  Masashi Tomimatsu  1 ,  Akari Ikeda  1 ,  Renya Chosokabe  1 ,  Shota Tanaka  1 ,  Yoshiaki Okada  1  2 ,  Yasushi Fujio  1  2  3 ,  Masanori Obana  1  2  3  4  5
Affiliations
  • 1. Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University.
  • 2. Center for Infectious Disease Education and Research (CiDER), Osaka University.
  • 3. Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University.
  • 4. Global Center for Medical Engineering and Informatics (MEI), Osaka University.
  • 5. Radioisotope Research Center, Institute for Radiation Sciences, Osaka University.
PMID: 38044094 DOI: 10.1248/bpb.b23-00482
Abstract

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.

Keywords
adenine–thymine-rich interactive domain-containing protein 5a (Arid5a); endothelial cell; interleukin (IL)-6; kidney injury; lipopolysaccharide (LPS); plasminogen activator inhibitor-1 (PAI-1).
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