Abstract:
Aflatoxin B1 (AFB1) is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,
particularly causing damages to kidney. Glomerular podocytes are terminally differentiated epithelial cells.
AFB1 induces podocyte inflammation, proteinuria and renal dysfunction. Studying the mechanism of AFB1-
induced podocyte inflammation and murine kidney dysfunction, we detected that AFB1 increased ubiquitindependent degradation of the transcription factor RelA through enhanced interaction of RelA with E3 ubiquitin
ligase tripartite motif containing 7 (TRIM7) in mouse podocyte clone-5 (MPC-5) and mouse glomeruli.
Reduction of RelA resulted in decreasing microRNA-9 (miR-9) and activating the chemokine receptor 4
(CXCR4), thioredoxin interacting protein (TXNIP), and NOD-like receptor pyrin domain-containing 3
(NLRP3) signaling axis (CXCR4/TXNIP/NLRP3 pathway), leading to podocyte inflammation. We also
determined that downregulation of miR-9 led to CXCR4 expression and the downstream TXNIP/NLRP3
pathway activation. Overexpression of miR-9 or deletion of CXCR4 suppressed AFB1-induced CXCR4/
TXNIP/NLRP3 pathway, resulting in alleviating podocyte inflammation and kidney dysfunction. Our findings
indicated that ubiquitin-dependent proteolysis of RelA, downregulation of miR-9, and activation of CXCR4/
TXNIP/NLRP3 pathway played an essential role in AFB1-induced glomerular podocyte inflammation. Our
study revealed a novel mechanism, via RelA, for the control of AFB1’s nephrotoxicity, leading to an effective
protection of food safety and public health.
