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

Cellular metabolic rates in the kidney are critical for maintaining normal 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...

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Bibliographic Details
Published in:American journal of physiology. Renal physiology 2021-05, Vol.320 (5), p.F706-F718
Main Authors: Osis, Gunars, Traylor, Amie M, Black, Laurence M, Spangler, Daryll, George, James F, Zarjou, Abolfazl, Verlander, Jill W, Agarwal, Anupam
Format: Article
Language:English
Subjects:
Acute Kidney Injury - enzymology
Acute Kidney Injury - genetics
Acute Kidney Injury - pathology
Adenine
Animals
Biomarkers - metabolism
Cell Hypoxia
Cells, Cultured
Dehydrogenases
Disease Models, Animal
Fermentation
Gene Expression Regulation, Enzymologic
Glycolysis
Humans
Hypoxia
Immunofluorescence
Immunohistochemistry
Ischemia
Isoenzymes
Isoforms
Kidney - enzymology
Kidney - pathology
Kidney diseases
L-Lactate dehydrogenase
L-Lactate Dehydrogenase - genetics
L-Lactate Dehydrogenase - metabolism
Lactic acid
Localization
Male
Metabolic rate
Mice
Mice, Inbred C57BL
NAD
NADH
Oxidative phosphorylation
Phosphorylation
Pyruvic acid
Renal function
Renal Insufficiency, Chronic - enzymology
Renal Insufficiency, Chronic - genetics
Renal Insufficiency, Chronic - pathology
Reperfusion
Time Factors
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Summary:Cellular metabolic rates in the kidney are critical for maintaining normal 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), whereas LDH isoform B (LDHB) catalyzes the opposite reaction. LDH is widely used as a potential injury marker as it is released from damaged cells into the urine and serum; however, the precise isoform-specific cellular localization of the enzyme along the nephron has not been characterized. By combining immunohistochemistry results and single-cell RNA-sequencing data on healthy mouse kidneys, we identified that LDHA is primarily expressed in proximal segments, whereas LDHB is expressed in the distal parts of the nephron. In vitro experiments in mouse and human renal proximal tubule cells showed an increase in LDHA following hypoxia with no change in LDHB. Using immunofluorescence, we observed that the overall expression of both LDHA and LDHB proteins decreased following renal ischemia-reperfusion injury as well as in the adenine-diet-induced model of chronic kidney disease. Single-nucleus RNA-sequencing analyses of kidneys following ischemia-reperfusion injury revealed a significant decline in the number of cells expressing detectable levels of and ; however, cells that were positive showed increased average expression postinjury, 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. Cellular release of lactate dehydrogenase (LDH) is being used as an injury marker; however, the exact localization of LDH within the nephron remains unclear. We show that LDH isoform A is expressed proximally, whereas isoform B is expressed distally. Both subunit expressions were significantly altered in models of acute kidney injury and chronic kidney disease. Our study provides new insights into basal and postinjury renal lactate metabolism.
ISSN:1931-857X
1522-1466
DOI:10.1152/ajprenal.00628.2020