Inhibition of RNA-Binding Protein Hu Antigen R (HuR) Prevents AKI-to-CKD Transition in Aristolochic Acid-Induced Nephropathy

Background: Acute kidney injury (AKI) is a significant risk factor for developing chronic kidney disease (CKD). The RNA-binding protein HuR is known to critically influence the progression of CKD, primarily by upregulating inflammation and facilitating fibrosis. We hypothesized that HuR might also play a pivotal role in the transition from AKI-to-CKD and inhibition of HuR could potentially mitigate persistent kidney damage. Methods: We utilized a model of aristolochic acid nephropathy, induced by the administration of aristolochic acid (AA), which is characterized by tubular atrophy and interstitial fibrosis, mirroring the AKI-to-CKD transition observed in humans. After optimizing the AA dosage, male mice aged at 10 weeks received AA injections of 1.5mg/kg BW daily for 4 consecutive days. Concurrently, these mice were treated either without or with HuR inhibitor KH3 (adminstered at 40mg/kg-BW daily) for 14 days. Normal mice recevied saline injections. Results: Repeated AA injections significantly increased HuR expression in the kidneys, particularly in tubular cells, which was effectively suppressed by KH3 treatment. AA-induced kidney injury was evidenced by elevated plasma levels of blood urea nitrogen and creatinine, along with decreased glomerular filtration rate and increased urinary albuminuria. Histological analyses revealed markedly tubular atrophy, apoptosis, capillary rarefaction, inflammatory cell infiltration and fibrosis. These findings were determined using periodic acid-Schiff and Masson’s trichrome staining, alongside immunofluorescent staining for markers including Tunel+, CD31+, alpha-smooth muscle actin, fibronectin, collagen III, and F4/80+. Treatment with KH3 mitigated these pathological changes in AA-injured mice. Additionally, the increased renal expression of NF-kBp65 and phosphorylated Akt- molecules implicated in AA-induced tubular cell DNA damage, apoptosis, and necrosis- along with gamma-H2AX, cleaved caspase-3, and PARP expression, were inhibited by KH3 treatment. Conclusion: Our findings demonstrate that elevated HuR levels in renal tubular cells, stimulated by AA, critically contribute to the progression from AKI-to-CKD. This effect is likely mediated through the HuR-cellular DNA signaling pathway. These results highlight the therapeutic potential of HuR inhibitors in treating AKI-to-CKD transition. Funding: NIDDK Support