RNA-binding protein HuR regulates the transition of septic AKI to CKD by modulating CD147.

Abstract

Septic acute kidney injury (AKI) is an important risk factor for developing chronic kidney disease (CKD). Hu antigen R (HuR) is recognized as a crucial modulator in inflammation. We hypothesized that elevated HuR contributes to the transition from septic AKI to CKD by promoting persistent inflammation and fibrosis, and inhibition of HuR may reverse septic kidney injury. Mice subjected to lipopolysaccharide (LPS) injections every other day were concurrently treated without or with either KH39 or niclosamide (NCS) for 7 days. Control mice received saline injections. Repeated LPS injections led to a significant increase in HuR expression in the kidneys, which was effectively suppressed by KH39 or NCS treatment. LPS-induced kidney injury was characterized by elevated plasma blood urea nitrogen levels and urinary albuminuria, along with histological signs of inflammatory cell infiltration and fibrosis, as determined by periodic acid-Schiff and Masson's trichrome staining, and immunofluorescent staining for markers such as α-smooth muscle actin, fibronectin, collagen III, and F4/80. Treatment with either KH39 or NCS mitigated these changes observed in LPS-injured kidneys. Additionally, increased expression of CD147, a molecule implicated in inflammatory cell recruitment and tubular injury, was inhibited by KH39 or NCS treatment. These effects on HuR and CD147 expression were further validated in vitro in cultured macrophages and tubular cells. This study suggests that HuR elevation in LPS-stimulated macrophages and kidney cells contributes to the progression of septic kidney injury, possibly through HuR-CD147 interactions, underscoring the therapeutic potential of HuR inhibitors for this condition.