Kidney Week

Abstract: FR-PO347

Alteration of Fatty Acid Oxidation in Proximal Tubular Epithelial Cells during Renal Fibrosis

Session Information

• Mechanisms Associated with Kidney Fibrosis - I
  November 03, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Chronic Kidney Disease (Non-Dialysis)

• 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

• Ding, Hao, Nanjing Medical University, Nanjing, JIANGSU , China

Hao Ding,

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

Junwei Yang,

Background

Chronic kidney diseases (CKD) generally lead to renal fibrosis and so far no effective therapeutic anti-fibrosis strategy is available. At the tubular cell scale, proximal tubular epithelial cells (PTCs) which prefer fatty acid as their energy source are the most energy-demanding cells in the body and involved in the process of interstitial fibrosis.

Methods

In this study, we employed mice with unilateral ureter obstruction (UUO) and TGFβ1-treated primary PTCs as two model systems. The Cre/loxP system was used to generate renal PTCs–specific CPT1α deletion mice (CPT1α^KO).

Results

Here we first demonstrated that a switch of metabolism from oxidative phosphorylation to aerobic glycolysis in mouse kidney with UUO surgery. We found rate-limiting enzymes and key transcription factors involved in FAO were reduced in fibrotic kidney and TGFβ1-treated primary PTCs. We uncovered that altered of FAO was associated with higher lipid accumulation in diseased renal and TGFβ1-treated primary PTCs. We also found that the enzymes and regulators of FAO were reduced in renal biopsy specimens of patients with CKD and was associated with the severity of renal interstitial fibrosis. PTCs-specific ablation of CPT1α resulted in a phenotype that body weight was lower compare with their control littermates. Kidney injury molecule-1, NAG enzyme in urine and blood urea nitrogen were increased within 4 months and recovery at 8 months. We noticed the expression of rate-limiting enzymes and key transcription factors involved in peroxisomal compartments pathway were up-regulated in kidneys of knockouts. In line with this, CPT1α^KO mice showed higher heat production compared to the controls which is indicative of proportion of energy expenditure derived from lipid oxidation in peroxisomal. Finally, inhibiting mitochondrial FAO of PTCs lead to up-regulation of peroxisomal FAO pathway.

Conclusion

In conclusion, our findings demonstrate altered of both mitochondrial and peroxisomal β-oxidation enzyme systems during the process of interstitial fibrosis. Furthermore, we found peroxisomal FAO pathway was compensatory up-regulated when mitochondrial FAO is shut down. Our results indicate that drugs that specifically restoring FAO may attenuate renal fibrosis.

Funding

• Government Support - Non-U.S.