Autophagy-Associated FIP200 Protects Renal Tubules Against Apoptosis Following Renal Ischemia-Reperfusion Injury
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Li, Yi, Department of Nephrology, Sichuan Provincial People’s Hospital, Sichuan Clinical Research Center for Kidney Diseases, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Wang, Li, Department of Nephrology, Sichuan Provincial People’s Hospital, Sichuan Clinical Research Center for Kidney Diseases, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
Group or Team Name
- National Natural Science Foundation of China (82270729, U21A20349) and Key R&D projects in Sichuan Province (2021YFS0372, and 2021YFS0370).
Acute kidney injury (AKI) easily progresses to chronic kidney diseases. Renal ischemia-reperfusion injury (IRI) is an important cause of AKI. The pathogenesis of renal IRI is complex, and its pathological characteristics mainly include renal tubular epithelial cell injury. Apoptosis is one of the main mechanisms of hypoxia-induced renal tubular epithelial cell death. Autophagy regulates apoptosis and plays a key role in the development of renal IRI. FAK family-interacting protein of 200 kDa (FIP200) is a crucial component of the ULK-1-Atg13-FIP200 complex formed in mammalian cells upon autophagy induction. However, the precise mechanisms of FIP200 in renal IRI-mediated AKI remains elusive.
The Billups hypoxic modular systemwas used to establish the hypoxia/reoxygenation (H/R) cell model in HK2 cells. Cells were maintained under hypoxia for 5 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, and 24 h, and then reoxygenated for 24 h. Cells in the control group were not subjected to hypoxia then reoxygenation. All animal studies were approved by the Ethics Committee of Sichuan Provincial People’s Hospital (approval No. L201735). Twenty-four wild-type mice were divided into 8 groups, and the renal pedicles of their left kidney were clamped with microvascular forceps. Then, 12 FIP200 conditional knockout (FIP200loxp-/loxp--Ggt cre/mice) mice in the renal tubular epithelial cell, in parallel to 12 wild-type mice, were randomly divided into renal IRI group and sham operation group.
The expression of the autophagy-related protein FIP200 was up-regulated in vivo and in vitro after renal IRI or hypoxia/reoxygenation (H/R). Mice with conditional FIP200 knockout in renal tubules showed severe renal tissue damage after IRI. Overexpression and knockdown of FIP200 in HK2 cells revealed its protective effects on H/R injury of renal tubular epithelial cells. FIP200 could interact with HMGB1 by immunoprecipitation assays and biolayer interferometry. FIP200 could induce autophagy by regulating the competitive binding of HMGB1 and autophagy-related factors.
Our data indicate that FIP200 has an important role in preventing renal tubular cell damage and death following renal IRI, and might be a novel potential target for prevention and treatment of AKI caused by IRI.