Abstract: FR-PO174
RNA-Binding Protein HuR Regulates the Progression of Septic AKI by Modulating CD147
Session Information
- AKI: Mechanisms - II
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Li, Davey, University of Utah Health, Salt Lake City, Utah, United States
- Tang, Anna, University of Utah Health, Salt Lake City, Utah, United States
- Sharma, Nisha, University of Utah Health, Salt Lake City, Utah, United States
- Huang, Yufeng, University of Utah Health, Salt Lake City, Utah, United States
Background
Septic AKI is one of the most common complications in critically ill patients with a high risk of developing CKD and no cause-specific treatment. Hu antigen R (HuR), an RNA-binding protein governing mRNA stability and translation, has been identified as a key modulator in inflammation. We hypothesized that the enhanced HuR/pro-inflammatory actor circuit is a crucial mechanism for the transition of septic AKI to CKD and inhibition of HuR may reverse septic kidney injury.
Methods
Sustained administration of LPS (5mg/kg BW, i.p. every other day)-induced mice (n=5/each group) were treated without or with HuR inhibitor, KH-39 (50mg/kg BW) or niclosamide (NCS, 10mg/kg BW) i.p. daily for 7 days. Normal mice injected with saline severed as controls.
Results
Repeated injection of LPS to mice developed chronic kidney damage, including increase plasma BUN levels and urinary albumin/creatinine ratio by 2.98 and 2.52-folds respectively. Histologically, LPS-injured kidneys showed accumulative inflammatory cells (including F4/80+ macrophages) infiltration and fibronectin (FN) & collagen (Col) deposition. Both a-SMA and FN as the markers of renal fibrosis were markedly increased by 6.1 and 9.73-folds respectively determined by Western blot. Notely, a significantly increased HuR expression was observed in diseased kidney, which was inhibited by HuR inhibitor, KH-39 or NCS. Immunofluoresent staining for HuR confirmed the Western blot measurement. In addition, CD147 expressed in tubular cells is involved in kidney disease mainly associated with increase inflammatory cell recruitment at site of injury. As expected, expression of CD147 was increased by 2.28-folds in LPS-injured kidney tubular cells determined by Western blot and IF staining. Interestingly, this increase was inhibited by KH-39 or NCS. Inhibition of HuR with KH-39 or NCS further largely reduced the elevated plasma BUN levels and albuminuria, and tubular injury, inflammation and tubulointerstitial fibrosis, compared to the untreated LPS-injured mice (P<0.05).
Conclusion
These results suggest that HuR is increased in LPS-injured kidneys and the progression of septic AKI to CKD induced by persistent inflammation is strongly reduced by HuR inhibition, at least, through downregulating CD147 expression. This study may provide a proof-of-concept for repurposing HuR inhibitor as a new therapy for septic kidney injury.
Funding
- NIDDK Support