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

Area of Science:

• Nephrology
• Immunology
• Molecular Biology

Background:

• Systemic inflammation causes organ dysfunction, including kidney injury.
• Plasminogen activator inhibitor-1 (PAI-1) plays a role in inflammatory kidney injury, but its regulation is unclear.
• Interleukin-6 (IL-6) induces PAI-1 in sepsis, and adenine-thymine-rich interactive domain-containing protein 5a (Arid5a) stabilizes IL-6.

Purpose of the Study:

• To investigate the role of the Arid5a/IL-6/PAI-1 signaling pathway in lipopolysaccharide (LPS)-induced kidney injury.
• To determine the cellular source of PAI-1 in LPS-treated kidneys.

Main Methods:

• Lipopolysaccharide (LPS) administration to C57BL/6J mice and human umbilical vein endothelial cells (HUVECs) and human kidney 2 (HK-2) cells.
• Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (qRT-PCR) for gene and protein expression analysis.
• Administration of a PAI-1 inhibitor (TM5441) and use of Arid5a knockout mice.

Main Results:

• LPS upregulated PAI-1 mRNA in mouse kidneys and PAI-1 in HUVEC supernatants, but not in HK-2 cells.
• Endothelial cells were identified as the primary source of PAI-1 elevation in LPS-treated kidneys.
• PAI-1 inhibition reduced kidney injury markers and downregulated IL-6 and Arid5a.
• IL-6 exacerbated LPS-induced kidney injury and PAI-1 expression.
• Arid5a knockout mice showed reduced IL-6 and PAI-1 expression after LPS treatment compared to wild-type mice.

Conclusions:

• The Arid5a/IL-6/PAI-1 signaling pathway forms a detrimental cycle in LPS-induced kidney injury.
• Endothelial cell-derived PAI-1 contributes significantly to inflammatory kidney damage.
• Targeting this pathway may offer therapeutic potential for inflammatory kidney diseases.