Kidney Week

Abstract: SA-PO839

The Role of CPT1α on Fatty Acid Metabolism and Development of Renal Fibrosis

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Yuan, Qi, Nanjing Medical University, Jiangsu Nanjing, China

Qi Yuan,

• Zhou, Yang, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China

Yang Zhou,

• Ding, Hao, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China

Hao Ding,

• Fang, Yi, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China

Yi Fang,

• Yang, Junwei, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China

Junwei Yang,

Background

Renal fibrosis is the common pathologic feature of chronic kidney disease (CKD). Proximal tubular epithelial cells (PTCs) prefer fatty acid as their energy source. Defective fatty acid oxidation plays a key role in kidney fibrosis development. CPT1α is the rate limiting enzyme that transport fatty acid into mitochondria. Moreover, CPT1α has a lysine succinyltransferase activity. In this study, we investigated the role of CPT1α in modulation of cellular fatty acid homeostasis in tubular epithelial cells during renal fibrosis.

Methods

Renal fibrosis was induced by folic acid (FA) injection. Relationship between renal fibrosis and expression of CPT1α was examined using renal biopsy samples from 30 patients and kidneys from FA mice. Mice with PTCs' specific ablation of CPT1α (KO) were generated and pharmacologic and genetic upregulation of CPT1α were used to investigate the role of CPT1α on renal fibrosis.

Results

Expression of CPT1α in proximal tubular epithelial cells was negatively correlated with the area of renal fibrosis in both human samples and FA model. Tubular CPT1α^KO mice experienced severe renal fibrosis and increased expressions of fibrotic markers, such as collagen I, fibronectin and vimentin than wild-type mice. While upregulation of CPT1α by administration of fenofibrate or transfection of CPT1α plasmid attenuated the accumulation of extracellular matrix and renal fibrosis in mice kidney. Moreover, upregulation of CPT1α increased the key enzymes of fatty acid metabolism, including ACAD, FASN, GPAT and GPD1. The decreased succinylation of the enzymes and regulators of fatty acid metabolism in fibrosis kidney were relieved by fenofibrate treatment.

Conclusion

These results demonstrate that CPT1α plays a major role in fatty acid metabolism disturbance in the tubular epithelial cells and contributes to renal fibrosis. Restoring the lysine succinyltransferase activity of CPT1α may provide novel therapeutic approach for kidney fibrosis.

Funding

• Government Support - Non-U.S.