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Abstract: PO2491

Deletion of Tubular Cpt1a Does Not Worsen Kidney Aging or Response to Injury

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Gewin, Leslie S., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Ivanova, Alla V., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Osaki, Yosuke, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Delgado, Rachel, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • de Caestecker, Mark P., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Zent, Roy, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Lantier, Louise, Vanderbilt University, Nashville, Tennessee, United States
Background

Proximal tubules (PT) preferentially use fatty acid oxidation to generate the energy necessary to support their high reasborptive capacity. Carnitine palmitoyltransferase 1 (CPT1) is required for long chain fatty acids to enter mitochondria, and CPT1a is considered the rate-limiting enzyme for PT fatty acid oxidation. CPT1a expression is decreased in kidney injury and its overexpression reduces fibrosis, so we hypothesized that Cpt1a deletion would exacerbate kidney aging and injury.

Methods

We inducibly deleted Cpt1a in adult mouse tubules using Pax8-rTTA;tetO-Cre mice and confirmed robust recombination. Mice were aged for 2 years or injured by either aristolochic acid nephropathy (AAN) or unilateral ureteral obstruction (UUO). Primary PT-enriched cell populations were generated from aged mice, and fatty acid-dependent respiration and glycolysis were measured using Seahorse bioflux analyzer.

Results

Old mice lacking tubular Cpt1a (Cpt1aCKO) had increased intracellular fatty acid accumulation (Oil Red O staining) and inflammation (F4/80 staining), but there were no significant differences in oxidative stress, fibrosis or renal function (GFR, proteinuria) compared with aged floxed controls. Similarly, Cpt1aCKO mice had no differences in tubular injury or fibrosis after either AAN or UUO-induced injury. Palmitate-dependent respiration was reduced but not blocked in primary cells from Cpt1aCKO aged mice, and glycolytic capacity was significantly increased. RNAseq from aged Cpt1aCKO revealed significantly upregulated genes in several pathways including PPARα that may compensate for Cpt1a loss.

Conclusion

Surprisingly, tubular deletion of Cpt1a did not worsen aging or response to kidney injury in mice, suggesting that compensatory responses can partially correct the metabolic impairment. A better understanding of these compensatory responses may inform future treatments for kidney injury.

Funding

  • NIDDK Support