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Abstract: SA-PO427

ALCAT1-Mediated Cardiolipin Remodeling Contributes to Podocyte Mitochondrial Dysfunction in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Fan, Yanqin, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
  • Hao, Yiqun, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
  • Ding, Guohua, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
Background

Recent studies suggested that mitochondrial damage resulting from abnormal cardiolipin remodeling was associated with the pathogenesis of diabetic kidney disease (DKD). AS a cardiolipin acyltransferase, ALCAT1 was confirmed to be involved in Parkinson's diseases and other aging-related diseases by regulating pathological CL remodeling. The purpose of this investigation was to determine the role of ALCAT1 in DKD.

Methods

We used db/db mice to conduct the in vivo experiments. Double immunolabeling and Western blots (WB) were performed to assess ALCAT1 distribution and expression in glomeruli. Mitochondrial structure was examined by transmission electron microscope (TEM). CL composition was assessed by lipidomics analysis. We cultured conditionally immortalized human podocytes to perform the in vitro studies. Lipidomics,TEM and WB analysis were similar to the in vivo study. Mitochondrial function was evaluated by mitochondrial membrane potential, mitochondrial ROS and ATP. The overexpression plasmids and siRNA were transfected to further investigate the changes of podocyte mitochondrial injury following overexpression or knockdown of ALCAT1.

Results

ALCAT1 expression was increased in glomerular podocytes of db/db mice and high-glucose (HG) cultured podocytes, accompanied by increased oxidized CL (ox-CL) and mitochondrial damage. ALCAT1 deficiency effectively blocked HG-induced ox-CL and podocyte mitochondria damage. In contrast, ALCAT1 upregulation enhanced ox-CL and mitochondria malfunction. Moreover, CL antioxidant SS-31 treatment markedly inhibited mitochondria dysfunction and cell injury. And SS-31 treatment could partly reverse the damage caused by ALCAT1 overexpression. We further found that ALCAT1 could mediate the key regulators of mitochondrial dynamics and mitophagy.

Conclusion

Our results demonstrated that ALCAT1-mediated cardiolipin remodeling played a crucial role in diabetic kidney disease and provided new insights for its treatment.

Funding

  • Government Support – Non-U.S.