Abstract: SA-PO291

Inability to Increase Fatty Acid Oxidation Following Renal Injury Worsens Renal Fibrosis

Session Information

Category: Cell Biology

  • 204 Extracellular Matrix Biology, Fibrosis, Cell Adhesion

Authors

  • Lee, Mardiana, Austin Health, Melbourne, Victoria, Australia
  • Mount, Peter F., Austin Health, Melbourne, Victoria, Australia
  • Katerelos, Marina, Austin Health, Melbourne, Victoria, Australia
  • Gleich, Kurt, Austin Health, Melbourne, Victoria, Australia
  • Power, David A., Austin Health, Melbourne, Victoria, Australia
Background

Recent studies have reported reduced expression of genes regulating fatty acid metabolism in fibrotic kidneys. However, the exact role of fatty acid metabolism in renal fibrosis is still unclear. To answer this question, we used mice with knock-in mutations of the regulatory S79 and S212 phosphorylation sites in acetyl CoA carboxylase 1 and 2 (ACC 1/2 KI) which have reduced ability to increase fatty acid oxidation when stressed. We aimed to determine whether reduced fatty acid oxidation contributes to renal fibrosis.

Methods

The folic acid nephropathy (FAN) and unilateral ureteric obstruction (UUO) models were induced in male ACC1/2KI mice and wild type (WT) controls. Mice were sacrificed at 14 and 7 days, respectively. Samples were studied by histomorphometry, Western blot and qRT-PCR.

Results

There was no difference in the appearance or function of ACC1/2KI kidneys at 8-10 weeks of age compared with WT. Reduced expression of genes controlling fatty acid oxidation was confirmed in the FAN model. In both FAN and UUO models there was increased accumulation of lipid by Oil Red O staining in ACC1/2KI mice (p<0.05 and p<0.01, respectively). Sirius red staining demonstrated increased fibrosis in ACC1/2KI mice in both models (p<0.05 and p<0.001)(Fig. 1). This was associated with increased expression of α-smooth muscle actin by Western blot (p<0.05) and qRT-PCR (p<0.01). In the FAN model, ACC1/2KI mice also had increased mRNA transcripts for Collagen I (P<0.05) by qRT-PCR compared with WT.

Conclusion


These data indicate that a reduced ability to regulate fatty acid oxidation in response to renal injury contributes to the development of renal fibrosis, and is not simply a consequence of injury. Regulation of fatty acid oxidation may be a potential therapeutic target in renal fibrosis.

Figure 1. Quantification of PicroSirius Red stained kidney sections analysis showing increased Collagen in KI UUO compared to WT UUO (***P<0.001).