PCK1 is a key regulator of metabolic and mitochondrial functions in renal tubular cells

Abstract

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.

A case of nephrocalcinosis in a 7‐month‐old with congenital hypothyroidism: Insights from targeted exome sequencing

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Hepatic ketone body regulation of renal gluconeogenesis

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