Acute and chronic kidney disease are responsible for large healthcare costs worldwide. During injury, kidney metabolism undergoes profound modifications in order to adapt to oxygen and nutrient shortage. Several studies highlighted recently the importance of these metabolic adaptations in acute as well as in chronic phases of renal disease, with a potential deleterious effect on fibrosis progression. Until recently, glucose metabolism in the kidney has been poorly studied, even though the kidney has the capacity to use and produce glucose, depending on the segment of the nephron. During physiology, renal proximal tubular cells use the beta-oxidation of fatty acid to generate large amounts of energy, and can also produce glucose through gluconeogenesis. In acute kidney injury, proximal tubular cells metabolism undergo a metabolic shift, shifting away from beta-oxidation of fatty acids and gluconeogenesis toward glycolysis. In chronic kidney disease, the loss of fatty acid oxidation is also well-described, and data about glucose metabolism are emerging. We here review the modifications of proximal tubular cells glucose metabolism during acute and chronic kidney disease and their potential consequences, as well as the potential therapeutic implications.

Phosphoenolpyruvate Carboxykinase 1 (PCK1, PEPCK-C) is a cytosolic enzyme converting oxaloacetate to phosphoenolpyruvate, with a potential role in gluconeogenesis, ammoniagenesis and cataplerosis in the liver. Kidney proximal tubule cells display a high expression of this enzyme, which importance is currently not well defined. We generated PCK1 kidney specific knock-out and knock-in mice under the tubular cell specific PAX8 promoter. We studied the effect of PCK1 deletion and overexpression at the renal level on tubular physiology under normal condition and during metabolic acidosis and proteinuric renal disease. PCK1 deletion led to hyperchloremic metabolic acidosis characterized by reduced but not abolished ammoniagenesis. PCK1 deletion also resulted in glycosuria, lactaturia and altered systemic glucose and lactate metabolism at baseline and during metabolic acidosis. Metabolic acidosis resulted in kidney injury in PCK1 deficient animals with decreased creatinine clearance and albuminuria. PCK1 further regulated energy production by the proximal tubule and PCK1 deletion decreased ATP generation. In proteinuric chronic kidney disease, mitigating PCK1 downregulation led to better renal function preservation. PCK1 is essential for kidney tubular cell acid base control, mitochondrial function and glucose/lactate homeostasis. Loss of PCK1 increases tubular injury during acidosis. Mitigating kidney tubular PCK1 downregulation during proteinuric renal disease improves renal function.