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Review
. 2018 Mar;38(2):111-120.
doi: 10.1016/j.semnephrol.2018.01.002.

The Warburg Effect in Diabetic Kidney Disease

Guanshi Zhang  1 , Manjula Darshi  1 , Kumar Sharma  2
Affiliations
Review

The Warburg Effect in Diabetic Kidney Disease

Guanshi Zhang et al. Semin Nephrol. 2018 Mar.

Abstract

Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in diabetic patients. Defining risk factors for DKD using a reductionist approach has proven challenging. Integrative omics-based systems biology tools have shed new insights in our understanding of DKD and have provided several key breakthroughs for identifying novel predictive and diagnostic biomarkers. In this review, we highlight the role of the Warburg effect in DKD and potential regulating factors such as sphingomyelin, fumarate, and pyruvate kinase muscle isozyme M2 in shifting glucose flux from complete oxidation in mitochondria to the glycolytic pathway and its principal branches. With the development of highly sensitive instruments and more advanced automatic bioinformatics tools, we believe that omics analyses and imaging techniques will focus more on singular-cell-level studies, which will allow in-depth understanding of DKD and pave the path for personalized kidney precision medicine.

Keywords: Diabetic kidney disease; aerobic glycolysis; metabolomics; mitochondrion; the Warburg effect.

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Conflict of interest statement

Conflict of interest statement: none.

Figures

Figure 1
Figure 1
Hyperglycemia enriches metabolic flux to glycolysis and five principal branches including the polyol pathway, pentose phosphate pathway (PPP), hexosamine pathway, protein kinase C (PKC) pathway, and advanced glycation end-products (AGE) pathway. Accumulation of four toxic glucose metabolites such as lactate, sorbitol, diacylglycerol (DAG), and methylglyoxal (MG) might contribute to the development of diabetic kidney disease. Abbreviations: 5-LGST, 5-lactoylglutathione; AR, aldose reductase; DHAP, dihydroxyacetone phosphate; ENO1, alpha-enolase; ETC, electron transport chain; F-6-P, fructose 6-phosphate; G-6-P, glucose 6-phosphate; G-3-P, glyceraldehyde 3-phosphate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAT, glutamine:fructose-6-phosphate amidotransferase; Gln, glutamine; Glu, glutamate; GluA-6-P, glucosamine-6-phosphate; GLO1, glyoxalase 1; HAGH, hydroxyacyl glutathione hydrolase; LDH, lactate dehydrogenase; OXPHOS, oxidative phosphorylation; PGM1, phosphoglucomutase-1; R-6-P, ribulose-5-phosphate; SORD, sorbitol dehydrogenase; TPI1, triosephosphate isomerase 1; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine.
Figure 2
Figure 2
Accumulation of sphingomyelin (SM), a potential mediator in enhancing glycolysis-derived ATP, leads to reduced phosphorylation of AMP-activated protein kinase (pAMPK) and mitochondrial function. Abbreviations: ADP, adenosine diphosphate; ATPase, ATP synthase; ETC, electron transport chain; G-6-P, glucose 6-phosphate; Mito, mitochondrial.
Figure 3
Figure 3
Fumarate accumulation, HIF-1α regulation, and glycolysis in renal cells with increased intracellular glucose. The reduced pAMPK enhances NOX4 leading to increased H2O2, which reduces fumarate hydratase (FH) levels and then leads to fumarate accumulation. Both increased H2O2 and fumarate contribute to ER stress and thereafter apoptosis. The increased fumarate suppresses HIF-PHD activity resulting in HIF-1α accumulation, which drives the metabolic flux to the glycolytic pathway (eg, through increased LDH) while suppresses oxidative phosphorylation (eg, through reduced PDK and increased PDH) and reduces mitochondrial O2·− HIF-1α also increases levels of glucose transport proteins (eg, GLUT1 and GLUT4) and growth factors (eg, VEGF and TGF-β). Abbreviations: ADP, adenosine diphosphate; G-6-P, glucose 6-phosphate; GLUT1/GLUT4, glucose transporters; LDH, lactate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PHD, prolyl hydroxylase; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor.
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