Chronic kidney disease (CKD) is a global health issue with increasing prevalence. Although current therapies have improved, slowing CKD progression remains a challenge. Metabolic alterations and mitochondrial dysfunction in tubular cells are increasingly recognized in CKD pathophysiology. The metabolic shift from gluconeogenesis to glycolysis during the progression of CKD has been highlighted, including the downregulation of key gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase 1 (PCK1). However, the specific role of PCK1 in kidney metabolism and repair remains incompletely understood.
In this study, we investigated the function of PCK1 in proximal tubule (PT) cell focusing on metabolism, mitochondrial homeostasis, and renal injury outcomes. Using mouse models with specific deletion or overexpression of PCK1 in tubular cells, we assessed the consequences of altered PCK1 expression under physiological conditions. We also examined its impact in multiple models of kidney injury, including ischemia-reperfusion injury, proteinuric nephropathy, and cisplatin-induced nephrotoxicity.
Loss of PCK1 in PT cells resulted in impaired cataplerosis leading to the accumulation of tricarboxylic acid cycle (TCA) intermediates, mitochondrial dysfunction, and reduced ATP production. Loss of PCK1 also induced a PT metabolic acidosis. This was associated with increased tubular damage, inflammation, and defective repair, promoting fibrosis and worsening renal function. In contrast, maintaining or restoring PCK1 activity preserved mitochondrial function and energy production. Preservation of PCK1 during renal injury improved renal function and histological lesions.
In humans, PCK1 loss was associated with a worse renal prognosis and evidence of mitochondrial dysfunctions.
Altogether, our work identifies cataplerosis as a critical component of tubular cell physiology and repair, with PCK1 acting as a key regulator and potential therapeutic target. Restoration of PCK1 activity enhances mitochondrial health, limits inflammation and fibrosis, and may slow the progression of CKD.
