TY - JOUR
T1 - Tubular CPT1A deletion minimally affects aging and chronic kidney injury
AU - Hammoud, Safaa
AU - Ivanova, Alla
AU - Osaki, Yosuke
AU - Funk, Steven
AU - Yang, Haichun
AU - Viquez, Olga
AU - Delgado, Rachel
AU - Lu, Dongliang
AU - Mignemi, Melanie Phillips
AU - Tonello, Jane
AU - Colon, Selene
AU - Lantier, Louise
AU - Wasserman, David
AU - Humphreys, Benjamin D.
AU - Koenitzer, Jeffrey
AU - Kern, Justin
AU - Caestecker, Mark de
AU - Finkel, Toren
AU - Fogo, Agnes
AU - Messias, Nidia
AU - Lodhi, Irfan J.
AU - Gewin, Leslie
N1 - Publisher Copyright:
: © 2024, Hammoud et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2024
Y1 - 2024
N2 - Kidney tubules use fatty acid oxidation (FAO) to support their high energetic requirements. Carnitine palmitoyltransferase 1A (CPT1A) is the rate-limiting enzyme for FAO, and it is necessary to transport long-chain fatty acids into mitochondria. To define the role of tubular CPT1A in aging and injury, we generated mice with tubule-specific deletion of Cpt1a (Cpt1aCKO mice), and the mice were either aged for 2 years or injured by aristolochic acid or unilateral ureteral obstruction. Surprisingly, Cpt1aCKO mice had no significant differences in kidney function or fibrosis compared with wild-type mice after aging or chronic injury. Primary tubule cells from aged Cpt1aCKO mice had a modest decrease in palmitate oxidation but retained the ability to metabolize long-chain fatty acids. Very-long-chain fatty acids, exclusively oxidized by peroxisomes, were reduced in kidneys lacking tubular CPT1A, consistent with increased peroxisomal activity. Single-nuclear RNA-Seq showed significantly increased expression of peroxisomal FAO enzymes in proximal tubules of mice lacking tubular CPT1A. These data suggest that peroxisomal FAO may compensate in the absence of CPT1A, and future genetic studies are needed to confirm the role of peroxisomal β-oxidation when mitochondrial FAO is impaired.
AB - Kidney tubules use fatty acid oxidation (FAO) to support their high energetic requirements. Carnitine palmitoyltransferase 1A (CPT1A) is the rate-limiting enzyme for FAO, and it is necessary to transport long-chain fatty acids into mitochondria. To define the role of tubular CPT1A in aging and injury, we generated mice with tubule-specific deletion of Cpt1a (Cpt1aCKO mice), and the mice were either aged for 2 years or injured by aristolochic acid or unilateral ureteral obstruction. Surprisingly, Cpt1aCKO mice had no significant differences in kidney function or fibrosis compared with wild-type mice after aging or chronic injury. Primary tubule cells from aged Cpt1aCKO mice had a modest decrease in palmitate oxidation but retained the ability to metabolize long-chain fatty acids. Very-long-chain fatty acids, exclusively oxidized by peroxisomes, were reduced in kidneys lacking tubular CPT1A, consistent with increased peroxisomal activity. Single-nuclear RNA-Seq showed significantly increased expression of peroxisomal FAO enzymes in proximal tubules of mice lacking tubular CPT1A. These data suggest that peroxisomal FAO may compensate in the absence of CPT1A, and future genetic studies are needed to confirm the role of peroxisomal β-oxidation when mitochondrial FAO is impaired.
UR - http://www.scopus.com/inward/record.url?scp=85188589019&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.171961
DO - 10.1172/jci.insight.171961
M3 - Article
C2 - 38516886
AN - SCOPUS:85188589019
SN - 2379-3708
VL - 9
JO - JCI Insight
JF - JCI Insight
IS - 6
M1 - 171961
ER -