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Metabolic requirements of the nephron

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Abstract

The mammalian kidney is a complex organ that has several metabolically active cell types to aid in waste filtration, salt-water balance, and electrolyte homeostasis in the body. These functions are done primarily through the nephron, which relies on strict regulation of various metabolic pathways. Any deviations in the metabolic profile of nephrons or their precursor cells called nephron progenitors can lead to renal pathologies and abnormal development. Metabolism encompasses the mechanisms by which cells generate intermediate molecules and energy in the form of adenosine triphosphate (ATP). ATP is required by all cells and is mainly generated through glycolysis, fatty acid oxidation, and oxidative phosphorylation. During kidney development, self-renewing or proliferating cells rely on glycolysis to a greater extent than the other metabolic pathways to supply energy, replenish reducing equivalents, and generate nucleotides. However, terminally differentiated cell types rely more heavily on fatty acid oxidation and oxidative phosphorylation performed in the mitochondria to fulfill energy requirements. Further, the mature nephron is comprised of distinct segments and each segment utilizes metabolic pathways to varying degrees depending on the specific function. This review will focus on major metabolic processes performed by the nephron during health and disease.

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References

  1. Little MH, McMahon AP (2012) Mammalian kidney development: principles, progress, and projections. Cold Spring Harb Perspect Biol 4:a008300

    PubMed  PubMed Central  Google Scholar 

  2. Schmidt U, Guder WG (1976) Sites of enzyme activity along the nephron. Kidney Int 9:233–242

    CAS  PubMed  Google Scholar 

  3. Guder WG, Wagner S, Wirthensohn G (1986) Metabolic fuels along the nephron: pathways and intracellular mechanisms of interaction. Kidney Int 29:41–45

    CAS  PubMed  Google Scholar 

  4. Liu J, Edgington-Giordano F, Dugas C, Abrams A, Katakam P, Satou R, Saifudeen Z (2017) Regulation of nephron progenitor cell self-renewal by intermediary metabolism. J Am Soc Neprol 28:3323–3335

    CAS  Google Scholar 

  5. Saifudeen Z, Dipp S, Stefkova J, Yao X, Lookabaugh S, El-Dahr SS (2009) p53 regulates metanephric development. J Am Soc Nephrol 20:2328–2337

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Mather A, Pollock C (2011) Glucose handling by the kidney. Kidney Int Suppl:S1–S6

  7. Suda T, Takubo K, Semenza GL (2011) Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 9:298–310

    CAS  PubMed  Google Scholar 

  8. Leisz S, Schulz K, Erb S, Oefner P, Dettmer K, Mougiakakos D, Wang E, Marincola FM, Stehle F, Seliger B (2015) Distinct von Hippel-Lindau gene and hypoxia-regulated alterations in gene and protein expression patterns of renal cell carcinoma and their effects on metabolism. Oncotarget 6:11395–11406

    PubMed  PubMed Central  Google Scholar 

  9. Wai T, Langer T (2016) Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab 27:105–117

    CAS  PubMed  Google Scholar 

  10. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Spencer NY, Stanton RC (2017) Glucose-6-phosphate dehydrogenase and the kidney. Nephrol Hypertens 26:43–49

    CAS  Google Scholar 

  12. Steer KA, Socher M, Gonzalez AM, McLean P (1982) Regulation of pathways of glucose metabolism in kidney. FEBS Lett 150:494–498

    CAS  PubMed  Google Scholar 

  13. Guder WG, Wirthensohn G (1979) Metabolism of isolated kidney tubules. Eur J Biochem 99:577–584

    CAS  PubMed  Google Scholar 

  14. Engelking L (2015) Gluconeogenesis. Textbook of Veternary Physiology. Academic Press, pp 225–230

  15. Gerich JE, Meyer C, Woerle HJ, Stumvoll M (2001) Renal gluconeogenesis. Diabetes Care 24:382–391

    CAS  PubMed  Google Scholar 

  16. Poirier Y, Antonenkov VD, Glumoff T, Hiltunen JK (2006) Peroxisomal beta-oxidation--a metabolic pathway with multiple functions. Biochim Biophys Acta 1763:1413–1426

    CAS  PubMed  Google Scholar 

  17. Forbes JM (2016) Mitochondria-power players in kidney function? Trends Endocrinol Metab 27:441–442

    CAS  PubMed  Google Scholar 

  18. Houten SM, Wanders RJ (2010) A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis 33:469–477

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ramday RR, Gandour RD, van der Leij FR (2001) Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 1546:21–43

  20. Bratic I, Trifunovic A (2010) Mitochondrial energy metabolism and ageing. Biochim Biophys Acta 1797:961–967

    CAS  PubMed  Google Scholar 

  21. Gautheron DC (1984) Mitochondrial oxidative phosphorylation and respiratory chain: review. J Inher Metab Dis 7:57–61

    CAS  PubMed  Google Scholar 

  22. Nelson N, Perzov N, Cohen A, Hagai K, Padler V, Nelson H (2000) The cellular biology of proton-motive force generation by v-ATPases. J Exp Biol 203:89–95

    CAS  PubMed  Google Scholar 

  23. Kung CP, Murphy ME (2016) The role of the p53 tumor suppressor in metabolism and diabetes. J Endocrinol 231:R61–R75

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Granata S, Dalla Gassa A, Tomei P, Lupo A, Zaza G (2015) Mitochondria: a new therapeutic target in chronic kidney disease. Nutr Metab 12:49

    Google Scholar 

  25. Gordan JD, Thompson CB, Simon MC (2007) HIF and c-Myc sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12:108–113

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, Davidoff O, Saifudeen Z, Haase VH (2017) Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development. Kidney Int 92:1370–1383

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Berkers CR, Maddocks OD, Cheung EC, Mor I, Vousden KH (2013) Metabolic regulation by p53 family members. Cell Metab 18:617–633

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Li Y, Liu J, Li W, Brown A, Baddoo M, Li M, Carroll T, Oxburgh L, Feng Y, Saifudeen Z (2015) p53 enables metabolic fitness and self-renewal of nephron progenitor cells. Development 142:1228–1241

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Schering B, Reinacher M, Schoner W (1986) Localization and role of pyruvate kinase isoenzymes in the regulation of carbohydrate metabolism and pyruvate recycling in rat kidney cortex. Biochim Biophys Acta 881:62–71

    CAS  PubMed  Google Scholar 

  30. (2016) Cancer Facts & Figures 2016. American Cancer Society, Atlanta, Ga. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2016.html

  31. Aminzadeh S, Vidali S, Sperl W, Kofler B, Feichtinger RG (2015) Energy metabolism in neuroblastoma and Wilms tumor. Transl Pediatr 4:20–32

    PubMed  PubMed Central  Google Scholar 

  32. Feichtinger RG, Neureiter D, Royer PB, Mayr JA, Zimmermann FA, Jones N, Koegler C, Ratschek M, Sperl W, Kofler B (2011) Heterogeneity of mitochondrial energy metabolism in classical triphasic Wilms tumor. Front Biosci 3:187–193

    Google Scholar 

  33. Hammer E, Ernst FD, Thiele A, Karanam NK, Kujath C, Evert M, Volker U, Barthlen W (2014) Kidney protein profiling of Wilms' tumor patients by analysis of formalin-fixed paraffin-embedded tissue samples. Clin Chim Acta 433:235–241

    CAS  PubMed  Google Scholar 

  34. Zawacka-Pankau J, Grinkevich VV, Hunten S, Nikulenkov F, Gluch A, Li H, Enge M, Kel A, Selivanova G (2011) Inhibition of glycolytic enzymes mediated by pharmacologically activated p53: targeting Warburg effect to fight cancer. J Biol Chem 286:41600–41615

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Dungwa JV, Hunt LP, Ramani P (2011) Overexpression of carbonic anhydrase and HIF-1alpha in Wilms tumours. BMC Cancer 11:390

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Baldewijns MM, van Vlodrop IJ, Vermeulen PB, Soetekouw PM, van Engeland M, de Bruine AP (2010) VHL and HIF signalling in renal cell carcinogenesis. J Pathol 221:125–138

    CAS  PubMed  Google Scholar 

  37. Singer K, Kastenberger M, Gottfried E, Hammerschmied CG, Buttner M, Aigner M, Seliger B, Walter B, Schlosser H, Hartmann A, Andreesen R, Mackensen A, Kreutz M (2011) Warburg phenotype in renal cell carcinoma: high expression of glucose-transporter 1 (GLUT-1) correlates with low CD8(+) T-cell infiltration in the tumor. Int J Cancer 128:2085–2095

    CAS  PubMed  Google Scholar 

  38. LaGory EL, Wu C, Taniguchi CM, Ding CC, Chi JT, von Eyben R, Scott DA, Richardson AD, Giaccia AJ (2015) Suppression of PGC-1alpha is critical for reprogramming oxidative metabolism in renal cell carcinoma. Cell Rep 12:116–127

  39. Wang SS, Gu YF, Wolf N, Stefanius K, Christie A, Dey A, Hammer RE, Xie WJ, Rakheja D, Pedrosa I, Carroll TJ, McKay RM, Kapur P, Brugarolas J (2014) Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis. Proc Natl Acad Sci U S A 111:16538–16543

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Granchi C, Minutolo F (2012) Anticancer agents that counteract tumor glycolysis. Chem Med Chem 7:1318–1350

    CAS  PubMed  Google Scholar 

  41. Ishimoto Y, Inagi R (2016) Mitochondria: a therapeutic target in acute kidney injury. Nephrol Dial Transplant 31:1062–1069

    CAS  PubMed  Google Scholar 

  42. Basu RK, Kaddourah A, Terrell T, Mottes T, Arnold P, Jacobs J, Andringa J, Goldstein SL, Prospective Pediatric AKIRG (2015) Assessment of worldwide acute kidney injury, renal angina and epidemiology in critically ill children (AWARE): study protocol for a prospective observational study. BMC Nephrol 16:24

    PubMed  PubMed Central  Google Scholar 

  43. Carafa V, Rotili D, Forgione M, Cuomo F, Serretiello E, Hailu GS, Jarho E, Lahtela-Kakkonen M, Mai A, Altucci L (2016) Sirtuin functions and modulation: from chemistry to the clinic. Clin Epigenetics 8:61

    PubMed  PubMed Central  Google Scholar 

  44. Yamamoto H, Schoonjans K, Auwerx J (2007) Sirtuin functions in health and disease. Mol Endocrinol 21:1745–1755

    CAS  PubMed  Google Scholar 

  45. Tran MT, Zsengeller ZK, Berg AH, Khankin EV, Bhasin MK, Kim W, Clish CB, Stillman IE, Karumanchi SA, Rhee EP, Parikh SM (2016) PGC1alpha drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 531:528–532

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wakino S, Hasegawa K, Itoh H (2015) Sirtuin and metabolic kidney disease. Kidney Int 88:691–698

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kitada M, Kume S, Koya D (2014) Role of sirtuins in kidney disease. Curr Opin Nephrol Hypertens 23:75–79

    CAS  PubMed  Google Scholar 

  48. Lan R, Geng H, Singha PK, Saikumar P, Bottinger EP, Weinberg JM, Venkatachalam MA (2016) Mitochondrial pathology and glycolytic shift during proximal tubule atrophy after ischemic AKI. J Am Soc Nephrol 27:3356–3367

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Niaudet P (1998) Mitochondrial disorders and the kidney. Arch Dis Child 78:387–390

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Che R, Yuan Y, Huang S, Zhang A (2014) Mitochondrial dysfunction in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 306:367–378

    Google Scholar 

  51. Rowe I, Boletta A (2014) Defective metabolism in polycystic kidney disease: potential for therapy and open questions. Nephrol Dial Transplant 29:1480–1486

    CAS  PubMed  Google Scholar 

  52. Baum M (2015) Overview of polycystic kidney disease in children. Curr Opin Pediatr 27:184–185

    PubMed  PubMed Central  Google Scholar 

  53. Rowe I, Chiaravalli M, Mannella V, Ulisse V, Quilici G, Pema M, Song XW, Xu H, Mari S, Qian F, Pei Y, Musco G, Boletta A (2013) Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nature Med 19:488–493

    CAS  PubMed  Google Scholar 

  54. Ishimoto Y, Inagi R, Yoshihara D, Kugita M, Nagao S, Shimizu A, Takeda N, Wake M, Honda K, Zhou J, Nangaku M (2017) Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease. Mol Cell Biol https://doi.org/10.1128/MCB.00337-17

  55. Flowers EM, Sudderth J, Zacharias L, Mernaugh G, Zent R, DeBerardinis RJ, Carroll TJ (2018) Lkb1 deficiency confers glutamine dependency in polycystic kidney disease. Nat Commun 9:814

    PubMed  PubMed Central  Google Scholar 

  56. (2013) Kidney Disease: Improving Global Outcomes (KDIGO) CKD work group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. . Kidney Int Suppl 3:1–150

  57. (CDC) CfDCaP (2014) National Chronic Kidney Disease Fact Sheet: general information and national estimates on chronic kidney disease in the United States, 2014

  58. Plantinga LC, Tuot DS, Powe NR (2010) Awareness of chronic kidney disease among patients and providers. Adv Chronic Kidney Dis 17:225–236

    PubMed  PubMed Central  Google Scholar 

  59. Becherucci F, Roperto RM, Materassi M, Romagnani P (2016) Chronic kidney disease in children. Clin Kidney J 9:583–591

    PubMed  PubMed Central  Google Scholar 

  60. Zhao J, Lupino K, Wilkins BJ, Qiu C, Liu J, Omura Y, Allred AL, McDonald C, Susztak K, Barish GD, Pei L (2018) Genomic integration of ERRγ-HNF1β regulates renal bioenergetics and prevents chronic kidney disease. Proc Natl Acad Sci U S A 11(E4910–495):E4910–E4919

    Google Scholar 

  61. Granata S, Zaza G, Simone S, Villani G, Latorre D, Pontrelli P, Carella M, Schena FP, Grandaliano G, Pertosa G (2009) Mitochondrial dysregulation and oxidative stress in patients with chronic kidney disease. BMC Genomics 10:388

    PubMed  PubMed Central  Google Scholar 

  62. Han SH, Wu MY, Nam BY, Park JT, Yoo TH, Kang SW, Park J, Chinga F, Li SY, Susztak K (2017) PGC-1alpha protects from notch-induced kidney fibrosis development. J Am Soc Nephrol 28:3312–3322

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Portilla D, Dai G, McClure T, Bates L, Kurten R, Megyesi J, Price P, Li S (2002) Alterations of PPARalpha and its coactivator PGC-1 in cisplatin-induced acute renal failure. Kidney Int 62:1208–1218

    CAS  PubMed  Google Scholar 

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Acknowledgements

KC is supported by the Children’s Hospital of Pittsburgh and by the NIH on a NIDDK F31 (DK116370) and SSL is supported by a NIDDK K01 (DK096996), and an R03 (DK110503).

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Correspondence to Sunder Sims-Lucas.

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Cargill, K., Sims-Lucas, S. Metabolic requirements of the nephron. Pediatr Nephrol 35, 1–8 (2020). https://doi.org/10.1007/s00467-018-4157-2

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