Acute kidney injury (AKI) predisposes survivors to chronic kidney disease (CKD), yet the post-injury mechanisms that drive maladaptive tubular repair are incompletely defined. The RNA-binding protein HuR (ELAVL1) stabilizes inflammatory and profibrotic transcripts but its role in AKI-to-CKD progression is unclear. We used aristolochic acid nephropathy (AAN) to test whether disrupting HuR–RNA interactions with the small molecule KH3 mitigates AKI-to-CKD transition. Single AA exposure produced dose-dependent AKI within 72 hours, while repeated AA induced a sustained CKD phenotype with tubulointerstitial fibrosis. AA increased HuR expression and cytoplasmic localization in injured tubular epithelial cells and in circulating exosomes. KH3 administration reduced BUN and creatinine, attenuated albuminuria, preserved tubular histology, and suppressed profibrotic and proinflammatory signaling in both acute and chronic AA models. Mechanistically, KH3 diminished AA-induced activation of NF-κBp65 and AKT, reduced markers of DNA damage, apoptosis, and senescence (γ-H2AX, cleaved PARP1/caspase-3, p21, p16-INK4a), and normalized ferroptosis-associated proteins in AA-treated human proximal tubular cells. These results identify HuR as a central post-transcriptional regulator of maladaptive tubular repair and provide proof-of-concept that pharmacologic targeting of HuR–RNA interactions can prevent progression from AKI to CKD.
Wang et al. (Fri,) studied this question.