Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction

Nature Medicine

Volumn 23, Issue 6, 2017, Pages 753-762

  Qi, Weier ^a   Keenan, Hillary A ^a   Li, Qian ^a   Ishikado, Atsushi ^a   Kannt, Aimo ^b   Sadowski, Thorsten ^b   Yorek, Mark A ^c   Wu, I Hsien ^a   Lockhart, Samuel ^d   Coppey, Lawrence J ^c   Pfenninger, Anja ^b   Liew, Chong Wee ^e   Qiang, Guifen ^e,f   Burkart, Alison M ^a   Hastings, Stephanie ^a   Pober, David ^a   Cahill, Christopher ^a   Niewczas, Monika A ^a   Israelsen, William J ^g   Tinsley, Liane ^a   Stillman, Isaac E ^h   Amenta, Peter S ^a   Feener, Edward P ^a   Vander Heiden, Matthew G ⁱ   Stanton, Robert C ^a   King, George L ^a   more..

^a HARVARD MEDICAL SCHOOL   (United States)

^b SANOFI AVENTIS DEUTSCHLAND GMBH   (Germany)

^c VETERANS AFFAIRS MEDICAL CENTER   (United States)

^d QUEEN'S UNIVERSITY BELFAST   (United Kingdom)

^e UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

^f INSTITUTE OF MATERIA MEDICA   (China)

^g UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^h BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

ⁱ MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 PHOSPHOFRUCTOKINASE; ALBUMIN; ALDEHYDE REDUCTASE; ALPHA SMOOTH MUSCLE ACTIN; ANTIDIABETIC AGENT; CD31 ANTIGEN; CREATININE; CYTOCHROME C OXIDASE; ENDOTHELIAL NITRIC OXIDE SYNTHASE; ENOLASE; FRUCTOSE BISPHOSPHATE ALDOLASE; GLUCOSE; GLYCERALDEHYDE 3 PHOSPHATE DEHYDROGENASE; GLYCOLYTIC ENZYME; GLYOXALASE; HEMOGLOBIN A1C; HYDROXYACYLGLUTATHIONE HYDROLASE; IDITOL DEHYDROGENASE; LACTATE DEHYDROGENASE; OXIDOREDUCTASE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; PHOSPHOGLUCOMUTASE; PHOSPHOGLYCERATE KINASE; PHOSPHOTRANSFERASE INHIBITOR; PYRUVATE KINASE; PYRUVATE KINASE M2; SORBITOL; TEPP 46; TRIOSEPHOSPHATE ISOMERASE; UNCLASSIFIED DRUG; NOS3 PROTEIN, MOUSE; PPARGC1A PROTEIN, MOUSE; REACTIVE OXYGEN METABOLITE;

ALBUMINURIA; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; APOPTOSIS; ARTICLE; CELL CULTURE; CONTROLLED STUDY; DIABETES MELLITUS; DIABETIC NEPHROPATHY; DISEASE COURSE; DISEASE DURATION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENZYME ACTIVATION; ESTIMATED GLOMERULAR FILTRATION RATE; GENE SILENCING; GLOMERULUS; GLYCOLYSIS; HISTOPATHOLOGY; HUMAN; HYPERGLYCEMIA; MITOCHONDRIAL BIOGENESIS; MITOCHONDRIAL RESPIRATION; MITOCHONDRION; MOUSE; NONHUMAN; PODOCYTE; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEOMICS; RENAL PROTECTION; UPREGULATION; AGED; ANIMAL; CELL LINE; EXPERIMENTAL DIABETES MELLITUS; FEMALE; FLUORESCENT ANTIBODY TECHNIQUE; GENETICS; KIDNEY; KNOCKOUT MOUSE; MALE; METABOLISM; METABOLOMICS; MIDDLE AGED; MITOCHONDRIAL MEMBRANE POTENTIAL; ORGANELLE BIOGENESIS; REAL TIME POLYMERASE CHAIN REACTION; VERY ELDERLY; WESTERN BLOTTING;

AGED; AGED, 80 AND OVER; ANIMALS; BLOTTING, WESTERN; CELL LINE; DIABETES MELLITUS; DIABETES MELLITUS, EXPERIMENTAL; DIABETIC NEPHROPATHIES; FEMALE; FLUORESCENT ANTIBODY TECHNIQUE; GENE KNOCKDOWN TECHNIQUES; GLUCOSE; GLYCOLYSIS; HUMANS; KIDNEY; KIDNEY GLOMERULUS; MALE; MEMBRANE POTENTIAL, MITOCHONDRIAL; METABOLOMICS; MICE; MICE, KNOCKOUT; MIDDLE AGED; MITOCHONDRIA; NITRIC OXIDE SYNTHASE TYPE III; ORGANELLE BIOGENESIS; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA COACTIVATOR 1-ALPHA; PODOCYTES; PROTEOMICS; PYRUVATE KINASE; REACTIVE OXYGEN SPECIES; REAL-TIME POLYMERASE CHAIN REACTION;

EID: 85018371570     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.4328     Document Type: Article

References (66)

1. Breyer, M.D. & Susztak, K. The next generation of therapeutics for chronic kidney disease. Nat. Rev. Drug Discov. 15, 568-588 (2016).
2. Khan, S.S. & Quaggin, S.E. Therapies on the horizon for diabetic kidney disease. Curr. Diab. Rep. 15, 111 (2015).
3. United States Renal Data System. 2015 USRDS Annual Data Report (USRDS, 2015).
4. Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615-1625 (2005).
5. Nishikawa, T. et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404, 787-790 (2000).
6. Dunlop, M. Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney Int. Suppl. 77, S3-S12 (2000).
7. Giacco, F. et al. Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice. Diabetes 63, 291-299 (2014).
8. Greene, D.A., Lattimer, S.A. & Sima, A.A. Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N. Engl. J. Med. 316, 599-606 (1987).
9. Lee, T.S., Saltsman, K.A., Ohashi, H. & King, G.L. Activation of protein kinase C by elevation of glucose concentration: proposal for a mechanism in the development of diabetic vascular complications. Proc. Natl. Acad. Sci. USA 86, 5141-5145 (1989).
10. Reidy, K., Kang, H.M., Hostetter, T. & Susztak, K. Molecular mechanisms of diabetic kidney disease. J. Clin. Invest. 124, 2333-2340 (2014).
11. Reddy, M.A. & Natarajan, R. Epigenetics in diabetic kidney disease. J. Am. Soc. Nephrol. 22, 2182-2185 (2011).
12. Fogo, A.B. The targeted podocyte. J. Clin. Invest. 121, 2142-2145 (2011).
13. Wang, W. et al. Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab. 15, 186-200 (2012).
14. Bolton, W.K. et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am. J. Nephrol. 24, 32-40 (2004).
15. Frank, R.N. The aldose reductase controversy. Diabetes 43, 169-172 (1994).
16. PKC-DRS Study Group. The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) multicenter randomized clinical trial. Diabetes 54, 2188-2197 (2005).
17. Pergola, P.E. et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N. Engl. J. Med. 365, 327-336 (2011).
18. Keenan, H.A. et al. Clinical factors associated with resistance to microvascular complications in diabetic patients of extreme disease duration: the 50-year medalist study. Diabetes Care 30, 1995-1997 (2007).
19. Sun, J.K. et al. Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the joslin 50-year medalist study. Diabetes Care 34, 968-974 (2011).
20. Tervaert, T.W. et al. Pathologic classification of diabetic nephropathy. J. Am. Soc. Nephrol. 21, 556-563 (2010).
21. Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278-1283 (2011).
22. Kung, C. et al. Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem. Biol. 19, 1187-1198 (2012).
23. Nakatsu, D. et al. L-cysteine reversibly inhibits glucose-induced biphasic insulin secretion and ATP production by inactivating PKM2. Proc. Natl. Acad. Sci. USA 112, E1067-E1076 (2015).
24. Palsson-McDermott, E.M. et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 21, 65-80 (2015).
25. Geraldes, P. et al. Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat. Med. 15, 1298-1306 (2009).
26. Khamaisi, M. et al. PKCδ inhibition normalizes the wound-healing capacity of diabetic human fibroblasts. J. Clin. Invest. 126, 837-853 (2016).
27. Mima, A. et al. Glomerular VEGF resistance induced by PKCδ/SHP-1 activation and contribution to diabetic nephropathy. FASEB J. 26, 2963-2974 (2012).
28. Israelsen, W.J. et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155, 397-409 (2013).
29. Varanita, T. et al. The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab. 21, 834-844 (2015).
30. Kanetsuna, Y. et al. Deficiency of endothelial nitric-oxide synthase confers susceptibility to diabetic nephropathy in nephropathy-resistant inbred mice. Am. J. Pathol. 170, 1473-1484 (2007).
31. Nakagawa, T. et al. Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J. Am. Soc. Nephrol. 18, 539-550 (2007).
32. Sharma, K. Mitochondrial hormesis and diabetic complications. Diabetes 64, 663-672 (2015).
33. Sharma, K. et al. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J. Am. Soc. Nephrol. 24, 1901-1912 (2013).
34. Kang, H.M. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37-46 (2015).
35. Dugan, L.L. et al. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J. Clin. Invest. 123, 4888-4899 (2013).
36. Susztak, K. Understanding the epigenetic syntax for the genetic alphabet in the kidney. J. Am. Soc. Nephrol. 25, 10-17 (2014).
37. Lunt, S.Y. et al. Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol. Cell 57, 95-107 (2015).
38. Dayton, T.L. et al. Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma. Genes Dev. 30, 1020-1033 (2016).
39. Luo, W. et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145, 732-744 (2011).
40. Shirai, T. et al. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J. Exp. Med. 213, 337-354 (2016).
41. Yang, W. & Lu, Z. Nuclear PKM2 regulates the Warburg effect. Cell Cycle 12, 3154-3158 (2013).
42. Yang, W. et al. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature 480, 118-122 (2011).
43. Christofk, H.R., Vander Heiden, M.G., Wu, N., Asara, J.M. & Cantley, L.C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452, 181-186 (2008).
44. Hitosugi, T. et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal. 2, ra73 (2009).
45. Chaneton, B. et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491, 458-462 (2012).
46. Breyer, M.D. et al. Mouse models of diabetic nephropathy. J. Am. Soc. Nephrol. 16, 27-45 (2005).
47. Brosius, F.C. III et al. Mouse models of diabetic nephropathy. J. Am. Soc. Nephrol. 20, 2503-2512 (2009).
48. Qi, Z. et al. Characterization of susceptibility of inbred mouse strains to diabetic nephropathy. Diabetes 54, 2628-2637 (2005).
49. Takahashi, T. & Harris, R.C. Role of endothelial nitric oxide synthase in diabetic nephropathy: lessons from diabetic eNOS knockout mice. J. Diabetes Res. 2014, 590541 (2014).
50. Gao, B.B., Stuart, L. & Feener, E.P. Label-free quantitative analysis of one-dimensional PAGE LC/MS/MS proteome: application on angiotensin II-stimulated smooth muscle cells secretome. Mol. Cell. Proteomics 7, 2399-2409 (2008).
51. Niewczas, M.A. et al. Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J. Am. Soc. Nephrol. 23, 507-515 (2012).
52. Sakairi, T. et al. Conditionally immortalized human podocyte cell lines established from urine. Am. J. Physiol. Renal Physiol. 298, F557-F567 (2010).
53. Shankland, S.J., Pippin, J.W., Reiser, J. & Mundel, P. Podocytes in culture: past, present, and future. Kidney Int. 72, 26-36 (2007).
54. Coppey, L.J. et al. Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 50, 1927-1937 (2001).
55. Li, B. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251-255 (2014).
56. Inoguchi, T. et al. Insulin's effect on protein kinase C and diacylglycerol induced by diabetes and glucose in vascular tissues. Am. J. Physiol. 267, E369-E379 (1994).
57. Massart, J., Zierath, J.R. & Chibalin, A.V. A simple and rapid method to characterize lipid fate in skeletal muscle. BMC Res. Notes 7, 391 (2014).
58. Brown, J.M. et al. Isomer-specific regulation of metabolism and PPAR signaling by CLA in human preadipocytes. J. Lipid Res. 44, 1287-1300 (2003).
59. Nemet, I., Varga-Defterdarović, L. & Turk, Z. Preparation and quantification of methylglyoxal in human plasma using reverse-phase high-performance liquid chromatography. Clin. Biochem. 37, 875-881 (2004).
60. Sweetwyne, M.T. et al. Notch1 and Notch2 in podocytes play differential roles during diabetic nephropathy development. Diabetes 64, 4099-4111 (2015).
61. Takemoto, M. et al. A new method for large scale isolation of kidney glomeruli from mice. Am. J. Pathol. 161, 799-805 (2002).
62. Advani, A. et al. Expression, localization, and function of the thioredoxin system in diabetic nephropathy. J. Am. Soc. Nephrol. 20, 730-741 (2009).
63. Isermann, B. et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat. Med. 13, 1349-1358 (2007).
64. Ma, L.J. et al. Divergent effects of low versus high dose anti-TGF-β antibody in puromycin aminonucleoside nephropathy in rats. Kidney Int. 65, 106-115 (2004).
65. Zhao, H.J. et al. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J. Am. Soc. Nephrol. 17, 2664-2669 (2006).
66. Pisania, A. et al. Quantitative analysis of cell composition and purity of human pancreatic islet preparations. Lab. Invest. 90, 1661-1675 (2010).