Foodborne toxin Aflatoxin B_(1)induced glomerular podocyte inflammation through proteolysis of RelA,downregulation of miR-9 and CXCR4/TXNIP/NLRP3 pathway

Aflatoxin B_(1)(AFB_(1))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.AFB_(1)induces podocyte inflammation,proteinuria and renal dysfunction.Studying the mechanism of AFB_(1)-induced podocyte inflammation and murine kidney dysfunction,we detected that AFB_(1)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 AFB_(1)-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 AFB_(1)-induced glomerular podocyte inflammation.Our study revealed a novel mechanism,via RelA,for the control of AFB_(1)’s nephrotoxicity,leading to an effective protection of food safety and public health.

CD36 promotes tubular ferroptosis by regulating the ubiquitination of FSP1 in acute kidney injury

Reactive oxidative species(ROos)production-driven ferroptosis plays a role in acute kidney injury(Akl).However,its exact molecular mechanism is poorly understood.Scavenger receptor CD36 has important roles in oxidizing lipids,lipid accumulation,metabolic syndrome,and insulin resistance in chronic kidney disease,but its roles remain unexplored in AKl.The present study investigated the role and mechanism of CD36 in regulating proximal tubular cell ferroptosis and AKl.The expression of CD36 was found to be significantly up-regulated in AKI renal tissues and correlated with renal function,which might serve as an independent biomarker for AKl patients.Moreover,in adult mice subjected to AKl,deletion of CD36(CD36-/-)induced tubular cell Ros accumulation,ferroptosis activation,and renal injury.Mechanistically,combining LC-MS/MS,co-IP,and ubiquitination analyses revealed that CD36 could specifically bind to ferroptosis suppressor protein 1(FSP1)and regulate its ubiquitination at sites K16 and K24,leading to FSP1 degradation and progression of ferroptosis in AKl.The present results emphasize a novel mechanism of CD36 in cisplatin-induced AKl.The discovery of the special CD36 roles in promoting ferroptosis and AKI development by regulating the ubiquitination of FSP1 in proximal tubular cells may be potential therapeutic targets for AKl.Moreover,CD36 may play a key role in the progression of AKl.Therefore,targeting CD36 may provide a promising treatment option for AKI.