Hints for a kidney lactate shuttle and lactomone
2021; American Physical Society; Volume: 320; Issue: 6 Linguagem: Inglês
10.1152/ajprenal.00160.2021
ISSN1931-857X
Autores Tópico(s)Renal and related cancers
ResumoEditorialHints for a kidney lactate shuttle and lactomoneDavid Sheikh-HamadDavid Sheikh-HamadDivision of Nephrology and Selzman Institute for Kidney Health, Department of Medicine, Baylor College of Medicine, Houston, TexasCenter for Translational Research on Inflammatory Diseases, Michael E. Debakey Veterans Affairs Medical Center, Houston, TexasPublished Online:02 Jun 2021https://doi.org/10.1152/ajprenal.00160.2021This is the final version - click for previous versionMoreSectionsPDF (198 KB)Download PDFDownload PDFPlus ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail Lactate, an end product of glycolysis, is produced and used continuously in many cells under both aerobic and anaerobic conditions, as a result of substrate supply and equilibrium dynamics (1). The metabolism of lactate is mediated by lactate dehydrogenase (LDH), which is highly expressed in the kidney; the location and identity of kidney LDH isoforms have not been clearly defined. There are four LDH genes and five LDH isoenzymes: LDH-1–LDH-5 (2). Kidney LDH is a tetramer encoded by Ldha and Ldhb genes [Ldhc is testis specific, whereas Ldhd is a mutant D isomer variant (2)]. The ratio of LDHA to LDHB in the tetramer determines the net direction of the reaction, pyruvate → lactate versus lactate → pyruvate (2); LDH-5 (four LDHA subunits) catalyzes the reaction of pyruvate to lactate, whereas LDH-1 (four LDHB subunits) predominately catalyzes the opposite reaction. However, all LDH isoenzymes are capable of either reaction, albeit at significantly different rates. When oxidative phosphorylation (OXPHOS) is impaired, as may occur following hypoxia, cells rely on glycolysis to produce energy, an inefficient way for ATP production, accompanied by the accumulation of pyruvate and NADH. Conversion of pyruvate to lactate by LDH-5 and regeneration of NAD+ from NADH are essential for glycolysis to continue so long as OXPHOS is impaired. LDH expression is altered following ischemic injury, where renal epithelial cells rely more on glycolysis to meet energy needs during the dedifferentiation and repair process (3). Thus, LDH is crucial for the recovery from renal injury and the maintenance of a healthy NAD+-to-NADH ratio, especially because the de novo synthesis and the recycling of NAD+ are inhibited in renal ischemia-reperfusion injury (4).Recent work by Osis and colleagues (5) suggests that LDHA and LDHB are differentially expressed along the nephron and display spatial and time-dependent responses to ischemic injury. The authors found that LDHA is primarily expressed in proximal nephron segments (PCT and PST) and localizes to the cytoplasm and the brush-border membrane, whereas LDHB is primarily expressed in the distal nephron (thick ascending limb, distal convoluted tubule, connecting tubule, and intercalated cells) and also localizes to the cytoplasm and the apical membrane. Both LDHA and LDHB decrease after ischemic acute kidney injury and recover later; LDHA declines early (day 1) followed by the LDHB decline on day 3 postinjury. Of interest, distal nephron expression of LDHB increases between days 3 and 7 after injury and normalizes by day 14. Both LDHA and LDHB proteins decrease globally in models of chronic kidney disease. In vitro studies in proximal tubule cells have shown increased LDHA following hypoxia without a change in LDHB. The authors’ data suggest that proximal tubules are lactate producers, whereas distal nephron segments are lactate consumers. In essence, lactate may be shuttled from the proximal nephron to the distal nephron as fuel or for signaling, a plausible occurrence physiologically, considering the anatomical proximity of these segments (proximal convoluted tubule and distal convoluted tubule, proximal straight tubule and thick ascending limb, proximal straight tubule and collecting duct, etc.).The concept of lactate shuttle was introduced by Brooks et al. (1), describing the movement of lactate between intracellular compartments or between cells/organs. In addition, lactate may be transported from the peripheral tissues to the liver, where it is converted to pyruvate by LDH through the Cori cycle. Lactate may also play a role in modulating inflammation, wound healing, redox signaling, gene expression, lipolytic control, memory formation, and cancer growth and metastasis (6, 7); some of these effects are mediated through activation of hydroxycarboxylic acid receptor 1 [G protein-coupled receptor-1 (GPR81)], which acts as a lactate sensor (6) on the plasma membrane and within intracellular organelles, downregulating cAMP to inhibit protein kinase A-mediated signaling (6, 7). These roles for lactate have given rise to the term “lactomone,” pertaining to lactate’s role as a signaling molecule. Increased intracellular levels of lactate induce the expression of genes involved in lactate removal, such as monocarboxylate transporters (MCTs), cytochrome c oxidase, and enzymes involved in lactate oxidation. In addition, lactate increases levels of peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1-α), suggesting that lactate stimulates mitochondrial biogenesis (7).Lactate plays a significant role in cancer biology; it induces stabilization of hypoxia-inducible factor (HIF)-1α and HIF-2α (8, 9), increasing HIF-1α-mediated vascular endothelial growth factor (VEGF) expression in cancer cells, and VEGF receptor-2 in neighboring endothelial cells, promoting angiogenesis (7). Moreover, lactate interferes with the production of interferon-γ by cytotoxic T cells and activates the proinflammatory IL-23/IL-17 pathway (10); these in turn suppress the immune response and promote inflammation, respectively, effects that support cancer cell growth. GPR81 expression is upregulated in many cancers, including cervical, breast, and liver cancer. In vitro expression of GPR81 promotes cancer cell survival, proliferation, migration, invasion, and resistance to chemotherapy and is associated with suppression of antitumor immunity by promoting programmed death-ligand 1 overexpression in lung cancer cell lines (7). In the cancer setting, glycolysis and lactate production are increased, and given the role of MCTs in lactate transport, these transporters are considered promising therapeutic targets in cancer therapy (7).To facilitate lactate shuttle, the involved cells/tissues express MCTs that mediate lactate transport; MCTs with high affinity to their substrates (MCT2; Km = 0.7 mM) are expressed in tissues that use lactate as fuel (brain and heart), whereas MCTs with low affinity to their substrates (MCT4; Km = 35 mM) are expressed in highly glycolytic tissues (astrocytes). An example for lactate shuttle exists in the brain; astrocytes express MCT4, which provides an exit pathway for lactate, whereas neurons express MCT2, providing an entry pathway for lactate as fuel. Lactate transfer from skeletal muscle to the heart is another example of the lactate shuttle, and during physical exercise, MCT proteins increase in the heart and skeletal muscle in proportion to exertion (7). Similarly, the kidney expresses a number of MCTs (11). MCT1 (Km = 3.5–10 mM) and MCT8 are detected in proximal tubule cells, whereas MCT7 and MCT2 localize to the thick ascending limb and the distal tubule. Expression of MCT2, which has a high affinity for lactate in the distal nephron, is consistent with the hypothesis proposed by Osis et al. (5), suggesting the existence of a lactate shuttle in the kidney, where lactate is produced in the proximal nephron and used as fuel in the distal nephron. The extent of “lactomone” functions within the kidney remains to be determined.GRANTSThis work was supported by the United States Department of Veterans Affairs (BX002006).DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSD.S. conceived and designed research; D.S. drafted manuscript; D.S. approved final version of manuscript.REFERENCES1. Brooks GA. Cell-cell and intracellular lactate shuttles. J Physiol 587: 5591–5600, 2009. doi:10.1113/jphysiol.2009.178350.Crossref | PubMed | ISI | Google Scholar2. Valvona CJ, Fillmore HL, Nunn PB, Pilkington GJ. The regulation and function of lactate dehydrogenase A: therapeutic potential in brain tumor. Brain Pathol 26: 3–17, 2016. doi:10.1111/bpa.12299.Crossref | PubMed | ISI | Google Scholar3. Ito K, Suda T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 15: 243–256, 2014. doi:10.1038/nrm3772.Crossref | PubMed | ISI | Google Scholar4. Poyan Mehr A, Tran MT, Ralto KM, Leaf DE, Washco V, Messmer J, Lerner A, Kher A, Kim SH, Khoury CC, Herzig SJ, Trovato ME, Simon-Tillaux N, Lynch MR, Thadhani RI, Clish CB, Khabbaz KR, Rhee EP, Waikar SS, Berg AH, Parikh SM. De novo NAD+ biosynthetic impairment in acute kidney injury in humans. Nat Med 24: 1351–1359, 2018. doi:10.1038/s41591-018-0138-z.Crossref | PubMed | ISI | Google Scholar5. Osis G, Traylor AM, Black LM, Spangler D, George JF, Zarjou A, Verlander JW, Agarwal A. Expression of lactate dehydrogenase A and B isoforms in the mouse kidney. Am J Physiol Renal Physiol 320: F706–F718, 2021. doi:10.1152/ajprenal.00628.2020.Link | ISI | Google Scholar6. Sun S, Li H, Chen J, Qian Q. Lactic acid: no longer an inert and end-product of Gglycolysis. Physiology (Bethesda) 32: 453–463, 2017. doi:10.1152/physiol.00016.2017.Link | ISI | Google Scholar7. Brooks GA. Lactate as a fulcrum of metabolism. Redox Biol 35: 101454, 2020. doi:10.1016/j.redox.2020.101454.Crossref | Google Scholar8. Lu H, Dalgard CL, Mohyeldin A, McFate T, Tait AS, Verma A. Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem 280: 41928–41939, 2005. doi:10.1074/jbc.M508718200.Crossref | PubMed | ISI | Google Scholar9. Pérez-Escuredo J, Dadhich RK, Dhup S, Cacace A, Van Hée VF, De Saedeleer CJ, Sboarina M, Rodriguez F, Fontenille M-J, Brisson L, Porporato PE, Sonveaux P. Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle 15: 72–83, 2016. doi:10.1080/15384101.2015.1120930.Crossref | PubMed | ISI | Google Scholar10. Shime H, Yabu M, Akazawa T, Kodama K, Matsumoto M, Seya T, Inoue N. Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway. J Immunol 180: 7175–7183, 2008. doi:10.4049/jimmunol.180.11.7175.Crossref | PubMed | ISI | Google Scholar11. Becker HM, Mohebbi N, Perna A, Ganapathy V, Capasso G, Wagner CA. Localization of members of MCT monocarboxylate transporter family Slc16 in the kidney and regulation during metabolic acidosis. Am J Physiol Renal Physiol 299: F141–F154, 2010. doi:10.1152/ajprenal.00488.2009.Link | ISI | Google ScholarAUTHOR NOTESCorrespondence: D. Sheikh-Hamad ([email protected]edu). Previous Back to Top Next FiguresReferencesRelatedInformationRelated articlesCould an intrarenal Cori cycle participate in the urinary concentrating mechanism? 30 Aug 2021American Journal of Physiology-Renal PhysiologyCited ByCould an intrarenal Cori cycle participate in the urinary concentrating mechanism?Lise Bankir30 August 2021 | American Journal of Physiology-Renal Physiology, Vol. 321, No. 3Reply to Bankir: the ever-expanding role of lactate in the kidneyGunars Osis and Anupam Agarwal30 August 2021 | American Journal of Physiology-Renal Physiology, Vol. 321, No. 3Reply to Bankir: does a Cori cycle exist in the kidney?David Sheikh-Hamad30 August 2021 | American Journal of Physiology-Renal Physiology, Vol. 321, No. 3 More from this issue > Volume 320Issue 6June 2021Pages F1028-F1029 Crossmark Copyright & PermissionsPublished by the American Physiological Societyhttps://doi.org/10.1152/ajprenal.00160.2021PubMed33938240History Received 21 April 2021 Accepted 26 April 2021 Published online 2 June 2021 Published in print 1 June 2021 PDF download Metrics Downloaded 637 times
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