Reply to Bankir: the ever-expanding role of lactate in the kidney

Multiple recent studies have transformed the perspective for lactate metabolism from being a static byproduct of glycolysis into a much more sophisticated molecule with roles ranging from an energy carrier to a signaling molecule (1). A recent publication from our group has shown the differential expression of lactate dehydrogenase isoform A (LDHA) and isoform B (LDHB) throughout the nephron (2). We observed that LDHA, which drives the conversion of pyruvate to lactate, is strongly expressed in the proximal parts of the nephron, whereas LDHB, which drives the opposite reaction, is predominant in the distal parts of the nephron (2).

In response to our work, Dr. Bankir highlighted the possibility of the existence of an intriguing mechanism of renal glucose-lactate metabolism expanding on the evolving role of renal lactate (3). The proposed mechanism of a kidney-specific Cori cycle relies on the preference of the proximal straight tubule to use the lactate for gluconeogenesis. Glucose could be secreted by apical Na⁺-glucose cotransporter 1 into the lumen of the tubule, which then reaches deeper areas of the kidney as filtrate travels where renal cells reabsorb secreted glucose and use glycolysis for their energy need. Glycolysis produces two molecules of ATP per glucose and two molecules of lactate, which then could be secreted in the interstitium contributing to the osmotic gradient and assisting in water reabsorption.

Such a lactate shuttle mechanism in the kidney was suggested in the accompanying Editorial by Dr. Sheikh-Hamad (4) wherein the existence of a similar shuttle in the brain was highlighted. In addition, the Editorial pointed to the presence of monocarboxylate transporters that could be the means of the lactate shuttle proposed by Dr. Bankir. The Editorial highlights the existence of specialized monocarboxylate transporters in the proximal tubule that could serve the role of lactate transporter out of the proximal tubules and into the distal segments of the nephron, further strengthening the existence of such a shuttle. Multiple transporters (SLC16A6 and SLC16A7) are present on the basolateral membrane of the thick ascending limb and have the potential to absorb lactate from the vasa recta and allow LDHB to convert it to pyruvate, which then could be converted to acetyl-CoA and used in mitochondria using oxidative metabolism (5). Consequently, thick ascending limb cells have been shown to have the highest metabolic activity throughout the nephron (6).

Dr. Bankir also proposes that if such a lactate cycle exists between proximal and distal segments, circulated lactate would also significantly contribute to osmotic regulation within the renal medulla. As one glucose molecule is broken down into two lactate molecules, it creates an increased osmotic pressure that would potentially assist in water retention. If the proposed lactate cycle does play a role in osmotic regulation, it would add another layer of clarity on water, salt, and urea balance in the kidney.

The Editorial by Dr. Sheikh-Hamad and the Letter from Dr. Bankir suggest the presence of lactate recycling mechanisms and open new areas for investigating energy metabolism, water regulation, and signaling mechanisms in the kidney.

GRANTS

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK59600 and a Predoctoral Fellowship Award from the American Heart Association (Grant 20PRE35200054).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

G.O. and A.A. drafted manuscript; G.O. and A.A. edited and revised manuscript; G.O. and A.A. approved final version of manuscript.