INCREASED FIBROSIS IN ACC KNOCKIN MICE FOLLOWING RENAL INJURY CONFIRMS A PATHOGENIC ROLE FOR REDUCED FATTY ACID OXIDATION

M LEE1,2, PF MOUNT1, M KATERELOS1, K GLEICH1, DA POWER1,2.

1Kidney Laboratory, Department of Nephrology, Austin Health, Heidelberg, VIC; 2Department of Medicine, The University of Melbourne, Heidelberg, VIC

Aim: To determine whether reduced fatty acid oxidation contributes to renal fibrosis.

Background: Expression of genes regulating fatty acid metabolism is reduced in kidneys with tubulointerstitial fibrosis. It is not known, however, whether this response contributes to fibrosis or is its consequence. To answer this question, we determined whether mice with knock-in mutations of regulatory phosphorylation sites in the major controllers of fatty acid oxidation, acetyl CoA carboxylase 1 and 2 (ACC1/2KI mice), have increased renal fibrosis following injury.

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). This was associated with increased expression of α-smooth muscle actin by Western blot and qRT-PCR (p<0.01). Increased fibrosis in the ACC1/2KI mice was confirmed by assay of Collagen I mRNA transcripts by qRT-PCR (P<0.05).

Conclusions: 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.

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