RNA-Binding Protein Hu Antigen R (HuR) Mediates Kidney Fibrosis in Mice with CKD Induced by Deoxycorticosterone Acetate-Salt and Angiotensin II Infusion

Background: The RNA-binding protein Hu antigen R (HuR) is pivotal in modulating mRNA turnover and translation of genes implicated in immune response and inflammation. Elevated HuR levels have been observed in patients with chronic kidney disease (CKD), yet its specific role in CKD pathogenesis remains elusive. This study aims to investigate the involvement of HuR in progressive renal injury resulting from deoxycorticosterone acetate-salt (DOCA) and angiotensin II (AII) infusion in mice, utilizing the HuR inhibitor KH3. Methods: Male mice at age of 12 weeks were subjected to DOCA+AII infusion along with 1% NaCl in drinking water. Subsequently, they were treated either with or without the HuR inhibitor, KH3 (administered at 40mg/kg-BW daily via intraperitoneal injection) (DOCA+AII+KH3) for a duration of 3 weeks. Control mice (NC) received saline injections without any infusion. Results: DOCA+AII infusion significantly increased HuR expression by 2.67 folds in the kidneys, a response effectively mitigated by KH3 treatment. Notably, KH3-treated mice exhibited a partial reduction in blood pressure compared to untreated DOCA+AII mice (SBP, 137.7±7.58 vs. 158.1±3.97 mmHg, P<0.05 vs. DOCA+AII). Additionally, KH3 treatment arrested the progression of albuminuria and led to a significant reduction in impaired renal function, kidney hypertrophy, and glomerular and tubulointerstitial fibrosis by 47.5%, 39.9%, 47.5% and 88.8% respectively (P<0.01), compared to untreated DOCA+AII mice. These improvements were accompanied by ameliorated podocyte injury, evidenced by reduced podocyte foot process effacement; and alleviated tubular injury, indicated by decreased mRNA and protein expression of KIM-1, NGAL and OPN in tubular cells, compared with untreated DOCA+AII mice. Furthermore, KH3 treatment significantly attenuated renal macrophage infiltration and the production of NF-kB-p65, Nox2, TGFß1 and Wisp1, markers of inflammation, oxidative stress and major profibrotic modulators induced by DOCA+AII infusion. Conclusion: Our findings suggest that HuR is upregulated in DOCA+AII induced kidney injury in mice and contributes to hypertensive, oxidative stress, inflammatory, and fibrotic pathways associated with CKD. Inhibition of HuR holds promise as a potential therapeutic strategy for CKD treatment. Funding: NIDDK Support