Expression of lactate dehydrogenase A and B isoforms in the mouse kidney

Abstract

Cellular metabolic rates in the kidney are critical for maintaining renal function. In a hypoxic milieu, cells rely on glycolysis to meet energy needs, resulting in the generation of pyruvate and NADH. In the absence of oxidative phosphorylation, the continuation of glycolysis is dependent on the regeneration of NAD+ from NADH accompanied by the fermentation of pyruvate to lactate. This reaction is catalyzed by lactate dehydrogenase (LDH) isoform A (LDHA), while isoform B (LDHB) catalyzes the opposite reaction. LDH is widely used as a potential injury marker, yet the precise isoform-specific cellular localization of the enzyme along the nephron has not been characterized. By combining immunohistochemistry and single-cell RNA sequencing data on healthy mouse kidneys we identified that LDHA is primarily expressed in proximal segments while LDHB is expressed in the distal parts of the nephron. In vitro studies in mouse and human renal proximal tubule cells show an increase in LDHA following hypoxia with no change in LDHB. We observed that the overall expression of both LDHA and LDHB decreased following renal ischemia-reperfusion injury (IRI) as well as in the adenine-diet induced model of chronic kidney disease. Single-nucleus RNA sequencing analyses of kidneys following IRI revealed a significant decline in the number of cells expressing Ldha and Ldhb, however, cells that were positive showed increased average expression post-injury which subsided during the recovery phase. These data provide information on the cell-specific expression of LDHA and LDHB in the normal kidney as well as following acute and chronic kidney disease.

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

“…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).…”

“…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).…”

Reply to Bankir: does a Cori cycle exist in the kidney?

“…Much like the lactate shuttle hypothesis proposed by Osis et al (1), the hypotheses proposed by Dr. Bankir are intriguing and require validation through animal experiments. Luckily, recent advances in molecular biology may provide the tools to answer these important questions.…”

“…In a letter to the Editor of the American Journal of Physiology-Renal Physiology, prompted by a recent publication by Osis et al (1) and a companion Editorial by Sheikh-Hamad (2), Dr. Bankir introduces the premise of an intrarenal Cori cycle. The Cori cycle describes the movement of lactate from the peripheral tissues, such as the muscle, to the liver, where it is converted to pyruvate by lactate dehydrogenase.…”

Could an intrarenal Cori cycle participate in the urinary concentrating mechanism?

“…In their recent study, Agarwal and colleagues showed how two forms of lactate dehydrogenase are distributed within the renal cortex and how they are affected by hypoxia (1). In the accompanying Editorial, David Sheikh-Hamad emphasized the importance of this "kidney lactate shuttle" (2).…”