Tubule-Specific Compensatory Responses to Cpt1a Deletion in Aged Mice.

KEY POINTS

Aging plus high fat diet suppresses expression of genes related to metabolism and fatty acid oxidation in the proximal tubules. Proximal tubules lacking have significant transcriptional increases in , peroxisomal fatty acid oxidation genes, and omega-oxidation genes. Distal convoluted tubules lacking have fewer changes in metabolic genes, but significantly downregulated expression of differentiation markers.

BACKGROUND

Fatty acid oxidation (FAO) is the preferred energy pathway in the proximal tubule (PT), and carnitine palmitoyltransferase 1A () is the rate-limiting enzyme of mitochondrial FAO. expression and FAO decrease after renal injury. Our recent work demonstrated that genetic deletion of tubular did not significantly worsen the response to injury or aging and did not completely block FAO, suggesting compensatory metabolic pathways. In addition, was most highly expressed in distal convoluted tubule (DCT), a segment not known for FAO. Therefore, we used single-nuclear RNA sequencing to explore a cell-specific responses to aging with high fat diet (HFD aging), to define compensatory metabolic pathways in PT segments lacking , and to determine the role of in the DCT.

METHODS

floxed () and tubule-specific conditional knockout () mice were aged for 2 years with HFD. Single-nuclear RNA-sequencing was performed on these HFD-aged mice and young controls.

RESULTS

HFD-aged mice had increased fibrosis, inflammation, and more injured PT cells than young mice. Whereas PT segments from HFD-aged mice had significant transcriptional changes in metabolism-related pathways, the DCT had more changes in inflammation-related pathways. Compared with floxed mice, HFD-aged mice had increased lipid deposition and increased inflammation, but no significant differences in fibrosis or renal function. PT segments from HFD-aged mice had significantly upregulated , a promoter of ketogenesis and FAO, and upregulated genes in peroxisomal FAO and omega-FAO (CYP4A family) pathways. DCT from HFD-aged mice had decreased expression of DCT-specific markers of cell differentiation.

CONCLUSIONS

The upregulated , peroxisomal FAO genes, and CYP4A genes may compensate for impaired mitochondrial metabolism of long chain fatty acids in PT cells lacking . Our data suggest that may be important in maintenance of cell differentiation for DCT.