Renal gluconeogenesis: a key metabolic hub in health and kidney disease

Gluconeogenesis, responsible for maintaining systemic glucose availability during fasting, has long been thought to be a process mainly performed by the liver. Over the past decades, physiological and molecular studies have established the kidney as a major site of endogenous glucose production. Renal gluconeogenesis occurs mainly in proximal tubular epithelial cells, where it integrates substrate utilization, hormonal signaling, and acid-base regulation to support systemic homeostasis. The kidney relies on distinct regulatory inputs and dynamically adapts gluconeogenic flux to nutritional state, metabolic acidosis, and interorgan metabolite exchange. As a highly metabolically active organ, it sustains the important energetic demands and differentiated state of proximal tubular cells through a high mitochondrial density. Renal gluconeogenesis is tightly coupled to ammoniagenesis and tricarboxylic acid cycle dynamics in addition to its contribution to glucose homeostasis, thus being a key determinant of mitochondrial integrity. Increasing evidence indicates that disruption of this metabolic program is a consistent feature of acute and chronic kidney disease, where suppression of gluconeogenesis accompanies epithelial dedifferentiation, mitochondrial dysfunction, and fibrotic remodeling. In this review, we synthesize current knowledge on the regulation and function of renal gluconeogenesis and discuss its emerging role as a central determinant of mitochondrial integrity, tubular resilience, and kidney disease progression.