Nephron Region-Specific Metabolic Considerations

Proximal Tubule

• Sodium transport and gluconeogenesis compete for ATP in the proximal convoluted tubule.
• Inhibition of Na+-K+-ATPase increases renal gluconeogenesis by 10-40% depending on the substrate.
• Stimulation of Na+-K+-ATPase activity with high extracellular K+ inhibits gluconeogenesis.
• Inhibition of the sodium pump induces a higher energy state of the cell, favoring energy-requiring synthetic processes.
• Increased perfusion rates decrease glucose production rate by 50%, whereas inhibition of apical transport increases glucose production rate.
• SGLT2 inhibitors reduce proximal gluconeogenesis by inhibiting SGLT2-mediated glucose uptake in diabetic mice.
• Mathematical models predict that TNa/Qo2 is 80% higher in the S3 segment of the proximal tubule due to the larger paracellular contribution to TNa.
• Inhibiting NHE3 or Na,K-ATPase reduces TNa, Qo2, and transport efficiency.

Thick Ascending Limb

• The TAL has a high rate of Na+ transport against a steep concentration gradient, high levels of Na+-K+-ATPase activity and expression, and 40% of its cytosolic volume occupied by mitochondria.
• The TAL requires oxidative metabolism to maintain cellular ATP levels and active Na+ reabsorption.
• During osmotic diuresis, medullary lactate doubles, suggesting increased glycolysis.
• Lactate production is increased in the distal segments, particularly in the TAL, during antimycin A incubation.

Cortical Collecting Duct

• CCD metabolism is characterized by the coexistence of different cell types: principal cells that reabsorb sodium and intercalated cells that secrete bicarbonate.
• Na+ reabsorption and HCO3- secretion in the CCD are dependent on oxidative phosphorylation but not on glycolysis or the hexose-monophosphate shunt pathways.
• Na+ reabsorption is best supported by a mixture of basolateral glucose and acetate, whereas HCO3- secretion is fully supported by either glucose or acetate.

Medullary Collecting Duct

• The outer medullary collecting duct (OMCD) has low sodium transport and few mitochondria.
• Bicarbonate secretion in the OMCD can be fully supported by endogenous substrates.
• The inner medullary collecting duct (IMCD) can maintain cellular ATP and respire normally in the absence of exogenous substrate.
• IMCD has a higher reliance on anaerobic metabolism but still takes advantage of oxidative metabolism to fully support transport.
• Both glycolysis and oxidative phosphorylation are required to maintain optimal Na+-K+-ATPase activity and preserve cellular K+ gradients in the IMCD.