Abstract: FR-PO1184
PCK1 Plays a Central Role in the Control of Metabolic and Mitochondrial Activities in Renal Tubular Cells
Session Information
- CKD: Mechanisms - 2
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Dalga, Delal, Universite de Geneve Faculte de Medecine, Geneve, Genève, Switzerland
- Verissimo, Thomas, Universite de Geneve Faculte de Medecine, Geneve, Genève, Switzerland
- Faivre, Anna, Universite de Geneve Faculte de Medecine, Geneve, Genève, Switzerland
- De Seigneux, Sophie M., Universite de Geneve Faculte de Medecine, Geneve, Genève, Switzerland
Background
During chronic kidney disease (CKD), renal gluconeogenesis is impaired, leading to metabolic dysfunction. Among the enzymes involved in gluconeogenesis, Phosphoenolpyruvate Carboxykinase 1 (PCK1), which facilitates the conversion of oxaloacetate to phosphoenolpyruvate, is rate-limiting. In this study, we hypothesize that the alteration of PCK1 expression in kidney proximal cells contributes to metabolic alterations during CKD and renal dysfunction, through modifications of acid-base balance and cataplerosis.
Methods
Using kidney tubular-specific knockout (KO) and knockin (KI) PCK1 mice models, we assessed the influence of PCK1 expression changes on renal function and kidney metabolism under physiological and pathological conditions. We utilized models of AKI (ischemia) and CKD (proteinuria and platinum toxicity).
Results
Under physiological conditions, PCK1 deletion leads to a loss of renal function and hyperchloremic metabolic acidosis. PCK1 inhibition also induces significant alterations in mitochondrial structure and function, as evidenced by Seahorse analysis and electron microscopy. Additionally, metabolomic analysis revealed that the loss of PCK1 results in decreased cataplerosis, leading to the accumulation of TCA cycle intermediates such as fumarate and malate in the kidney, thereby impeding the TCA cycle. In models of AKI and non-diabetic CKD, PCK1 deletion exacerbated renal dysfunction and mortality. Conversely, in two models of non-diabetic CKD, restoration of PCK1 in kidney tubular cells improved renal function, reduced tubular injury, and slowed fibrosis progression. Similarly, PCK1 restoration mitigated mitochondrial damage by promoting TCA cataplerosis.
Conclusion
PCK1 is essential for maintaining renal tubular acid-base balance, mitochondrial energy production, and TCA cataplerosis. Restoring PCK1 could be a crucial target for preventing mitochondrial dysfunction and the progression of kidney disease during CKD.