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Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.

ABSTRACT: Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.

SUBMITTER: Kang HM

PROVIDER: S-EPMC4444078 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.

Kang Hyun Mi HM Ahn Seon Ho SH Choi Peter P Ko Yi-An YA Han Seung Hyeok SH Chinga Frank F Park Ae Seo Deok AS Tao Jianling J Sharma Kumar K Pullman James J Bottinger Erwin P EP Goldberg Ira J IJ Susztak Katalin K

Nature medicine 20141201 1

Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had l ...[more]

PMID: 25419705

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Project description:Background Defects in the renal fatty acid ?-oxidation pathway have been implicated in the development of renal fibrosis. Our group has developed a therapeutic vaccine targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), named PCSK9Q?-003. In this study, we investigated the potential effectiveness of the PCSK9Q?-003 vaccine on hypercholesterolemia with renal fibrosis. Methods and Results The low-density lipoprotein receptor+/- male mice fed with a high-cholesterol (1%) Western diet were randomly assigned into 4 groups: the sham group (or the control group), the phosphate-buffered saline group, the Q? virus-like particles group and the PCSK9Q?-003 vaccine group. Mice of the PCSK9Q?-003 group were injected with the PCSK9Q?-003 vaccine (100 ?g/time) every 2 or 4 weeks. The mice were administered with either unilateral ureteral obstruction for 2 weeks or N-nitro-l-arginine methyl ester (50 mg/kg per day) for 6 weeks to establish a renal fibrosis model. Compared with the other 3 groups, the PCSK9Q?-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in low-density lipoprotein receptor+/- mice with hypercholesterolemia. Compared with the phosphate-buffered saline and Q? virus-like particles groups, the PCSK9Q?-003 vaccine improved hepatic steatosis and renal function. Histology analysis showed that the PCSK9Q?-003 vaccine significantly ameliorated renal lipid accumulation and renal fibrosis. Moreover, the PCSK9Q?-003 vaccine obviously upregulated the expression of low-density lipoprotein receptor, very-low-density lipoprotein receptor, sterol-regulatory element binding protein 2, and fatty acid ?-oxidation-related factors, and ameliorated renal fibrosis-related molecules both in the unilateral ureteral obstruction and N-nitro-l-arginine methyl ester models. Conclusions This study suggested that the PCSK9Q?-003 vaccine improved renal lipid accumulation and renal fibrosis by regulating fatty acid ?-oxidation, which may provide a promising method for treating hypercholesterolemia with renal fibrosis.

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Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.

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Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.

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