Abstract: PO0339
Limonin Protects Against AKI by Targeting ERK Signaling
Session Information
- AKI: Mechanisms of Injury
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Zhou, Xianke, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, Gaungdong, China
- Hong, Xue, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, Gaungdong, China
- Li, Dier, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, Gaungdong, China
- Zhong, Menghua, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, Gaungdong, China
- Fu, Haiyan, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, Gaungdong, China
Background
Acute kidney injury (AKI) is characterized by tubular cell injury, vascular dysfunction, and inflammation. As a key pathological event, sustained inflammation in AKI plays a critical role in accelerating disease progression. In the clinic, there are no effective therapeutic strategies to prevent AKI by thus far. We previously reported, Limonin, a member of the class of compounds known as furanolactones possesses potent anti-inflammatory effects in multiple auto-immune diseases. Whether Limonin could serve as a candidate to preserve renal function after AKI remains unclear.
Methods
Kidney ischemia-reperfusion injury (IRI) was employed to induce AKI in mice. Limonin was pretreated in mice two days before IRI. A molecular docking study and thermal shift assays were performed to determine the binding capacity between Limonin and key targets. In vivo and in vitro molecular experimental pathology studies were applied.
Results
After ischemic AKI, pretreatment of Limonin preserved kidney functions, ameliorated tubular injury, and repressed inflammation in the diseased kidneys, compared to the vehicles. In structure, we identified Limonin has active binding sites for 38 significant target proteins, including ERK. A molecular docking study demonstrated a high binding affinity between ERK2 and Limonin, which was confirmed by the temperature- and dose-dependent cellular thermal shift assays. In vivo, we further revealed that Limonin activated ERK signaling pathway and then promoted tubular cell proliferation and reduced cell apoptosis after AKI. In vitro, blockade of ERK signaling abolished the abilities of Limonin in preventing tubular cell apoptosis under hypoxia conditions.
Conclusion
Our results indicated that Limonin is a novel ERK activator. Its therapeutic effect on murine AKI paved a new avenue for AKI intervention in the clinic.
Funding
- Government Support – Non-U.S.