Dysregulation of SRSF3/circSAMD4/CIRBP Axis Promotes Iodinated Contrast-induced Acute Kidney Injury

TL;DR

A new mechanism involving circSAMD4, CIRBP, and SRSF3 contributes to kidney injury caused by iodinated contrast agents.

Contribution

The study identifies a novel regulatory axis (SRSF3/circSAMD4/CIRBP) involved in contrast-induced acute kidney injury.

Findings

circSAMD4 is upregulated in kidney cells during contrast-induced injury and promotes cell death.

circSAMD4 inhibits CIRBP's nuclear import, and CIRBP deletion reduces kidney injury.

SRSF3 downregulation drives circSAMD4 upregulation, linking it to kidney function decline.

Abstract

Iodinated contrast agents are a common cause of contrast-induced acute kidney injury (CI-AKI), yet the underlying mechanisms remain unclear. We found that circSAMD4 is markedly upregulated in renal tubular epithelial cells (RTECs) from iohexol-induced CI-AKI mice and patients diagnosed with acute tubular injury (ATI). Silencing circSAMD4 alleviated kidney injury and tubular cell death in CI-AKI mice, whereas its overexpression promoted apoptosis in iohexol-treated RTECs. Mechanistically, circSAMD4 binds to cold-inducible RNA-binding protein (CIRBP) and inhibits its nuclear import. Renal tubule-specific Cirbp deletion mitigated CI-AKI, while CIRBP overexpression abolished the protective effects of circSAMD4 knockdown against iohexol-induced apoptosis. CircSAMD4 upregulation in iohexol-treated RTECs was driven by serine/arginine-rich splicing factor 3 (SRSF3) downregulation. Similar molecular alterations in clinical samples correlated with kidney function decline. These findings identify the SRSF3/circSAMD4/CIRBP axis as a novel pathogenic mechanism in CI-AKI and highlight circSAMD4 as a promising therapeutic target.

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