1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Physiology
  4. Volume 86, 2024
  5. Article

Annual Review of Physiology

Volume 86, 2024

Metabolic Rewiring and Communication: An Integrative View of Kidney Proximal Tubule Function

Abstract

The kidney proximal tubule is a key organ for human metabolism. The kidney responds to stress with altered metabolite transformation and perturbed metabolic pathways, an ultimate cause for kidney disease. Here, we review the proximal tubule's metabolic function through an integrative view of transport, metabolism, and function, and embed it in the context of metabolome-wide data-driven research. Function (filtration, transport, secretion, and reabsorption), metabolite transformation, and metabolite signaling determine kidney metabolic rewiring in disease. Energy metabolism and substrates for key metabolic pathways are orchestrated by metabolite sensors. Given the importance of renal function for the inner milieu, we also review metabolic communication routes with other organs. Exciting research opportunities exist to understand metabolic perturbation of kidney and proximal tubule function, for example, in hypertension-associated kidney disease. We argue that, based on the integrative view outlined here, kidney diseases without genetic cause should be approached scientifically as metabolic diseases.

Keyword(s): AKI, amino acids, CKD, diabetes, fatty acid metabolism, gluconeogenesis, glycolysis, ketone body metabolism, SGLT2
Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-042222-024724
2024-02-12
2024-04-27
Loading full text...

Full text loading...

/deliver/fulltext/physiol/86/1/annurev-physiol-042222-024724.html?itemId=/content/journals/10.1146/annurev-physiol-042222-024724&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Smith HW. 1953. From Fish to Philosopher: The Story of Our Internal Environment Boston: Little, Brown
  2. 2.
    Zhuo JL, Li XC. 2013. Proximal nephron. Compr. Physiol. 3:31079–1123
     [Google Scholar]
  3. 3.
    Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB et al. 2008. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:1112–23
     [Google Scholar]
  4. 4.
    Clark JZ, Chen L, Chou C-L, Jung HJ, Lee JW, Knepper MA. 2019. Representation and relative abundance of cell-type selective markers in whole-kidney RNA-Seq data. Kidney Int. 95:4787–96
     [Google Scholar]
  5. 5.
    Braun F, Rinschen M, Buchner D, Bohl K, Plagmann I et al. 2020. The proteomic landscape of small urinary extracellular vesicles during kidney transplantation. J. Extracell. Vesicles 10:1e12026
     [Google Scholar]
  6. 6.
    Limbutara K, Chou C-L, Knepper MA. 2020. Quantitative proteomics of all 14 renal tubule segments in rat. J. Am. Soc. Nephrol. 31:61255–66
     [Google Scholar]
  7. 7.
    Lee JW, Chou C-L, Knepper MA. 2015. Deep sequencing in microdissected renal tubules identifies nephron segment-specific transcriptomes. J. Am. Soc. Nephrol. 26:112669–77
     [Google Scholar]
  8. 8.
    Rinschen MM, Limbutara K, Knepper MA, Payne DM, Pisitkun T. 2018. From molecules to mechanisms: functional proteomics and its application to renal tubule physiology. Physiol. Rev. 98:42571–2606
     [Google Scholar]
  9. 9.
    Johnson CH, Ivanisevic J, Siuzdak G. 2016. Metabolomics: beyond biomarkers and towards mechanisms. Nat. Rev. Mol. Cell Biol. 17:7451–59
     [Google Scholar]
  10. 10.
    Rinschen MM, Ivanisevic J, Giera M, Siuzdak G. 2019. Identification of bioactive metabolites using activity metabolomics. Nat. Rev. Mol. Cell Biol. 20:6353–67
     [Google Scholar]
  11. 11.
    Schranner D, Kastenmüller G, Schönfelder M, Römisch-Margl W, Wackerhage H. 2020. Metabolite concentration changes in humans after a bout of exercise: a systematic review of exercise metabolomics studies. Sports Med. Open 6:111
     [Google Scholar]
  12. 12.
    Pruijm M, Hofmann L, Maillard M, Tremblay S, Glatz N et al. 2010. Effect of sodium loading/depletion on renal oxygenation in young normotensive and hypertensive men. Hypertension 55:51116–22
     [Google Scholar]
  13. 13.
    Hansell P, Welch WJ, Blantz RC, Palm F. 2013. Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension. Clin. Exp. Pharmacol. Physiol. 40:2123–37
     [Google Scholar]
  14. 14.
    Bignon Y, Wigger L, Ansermet C, Weger BD, Lagarrigue S et al. 2023. Multiomics reveals multilevel control of renal and systemic metabolism by the renal tubular circadian clock. J. Clin. Investig. 133:8e167133
     [Google Scholar]
  15. 15.
    Costello HM, Gumz ML. 2021. Circadian rhythm, clock genes, and hypertension: recent advances in hypertension. Hypertension 78:51185–9616
     [Google Scholar]
  16. 16.
    Mohandas R, Douma LG, Scindia Y, Gumz ML. 2022. Circadian rhythms and renal pathophysiology. J. Clin. Investig. 132:3e148277
     [Google Scholar]
  17. 17.
    Harris AN, Weiner ID. 2021. Sex differences in renal ammonia metabolism. Am. J. Physiol. Ren. Physiol. 320:1F55–60
     [Google Scholar]
  18. 18.
    Melsom T, Norvik JV, Enoksen IT, Stefansson V, Mathisen UD et al. 2022. Sex differences in age-related loss of kidney function. J. Am. Soc. Nephrol. 33:101891–1902
     [Google Scholar]
  19. 19.
    Wen Y, Qi H, Mariager CØ, Nielsen PM, Bertelsen BL et al. 2020. Sex differences in kidney function and metabolism assessed using hyperpolarized [1-13C]pyruvate interleaved spectroscopy and nonspecific imaging. Tomography 6:15–13
     [Google Scholar]
  20. 20.
    Shankland SJ, Wang Y, Shaw AS, Vaughan JC, Pippin JW, Wessely O. 2021. Podocyte aging: why and how getting old matters. J. Am. Soc. Nephrol. 32:112697–2713
     [Google Scholar]
  21. 21.
    Li Q, McDonough AA, Layton HE, Layton AT. 2018. Functional implications of sexual dimorphism of transporter patterns along the rat proximal tubule: modeling and analysis. Am. J. Physiol. Ren. Physiol. 315:3F692–700
     [Google Scholar]
  22. 22.
    Harris AN, Lee H-W, Fang L, Verlander JW, Weiner ID. 2019. Differences in acidosis-stimulated renal ammonia metabolism in the male and female kidney. Am. J. Physiol. Ren. Physiol. 317:4F890–905
     [Google Scholar]
  23. 23.
    Goldstein L, Perlman DF. 1985. Renal oxidative metabolism and ammoniagenesis. Contrib. Nephrol. 47:170–75
     [Google Scholar]
  24. 24.
    Klahr S, Hamm LL, Hammerman MR, Mandel LJ. 2011. Renal metabolism: integrated responses. Comprehensive Physiology2263–2333 Hoboken, NJ: John Wiley & Sons
     [Google Scholar]
  25. 25.
    Vallon V, Verma S. 2021. Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annu. Rev. Physiol. 83:503–28
     [Google Scholar]
  26. 26.
    Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL et al. 2019. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl. J. Med. 380:242295–2306
     [Google Scholar]
  27. 27.
    Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ et al. 2020. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383:151413–24
     [Google Scholar]
  28. 28.
    Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T et al. 2020. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 383:151436–46
     [Google Scholar]
  29. 29.
    The EMPA-KIDNEY Collaborative Group 2023. Empagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 388:2117–27
     [Google Scholar]
  30. 30.
    Torosyan R, Huang S, Bommi PV, Tiwari R, An SY et al. 2021. Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway. Cell Rep. 36:7109547
     [Google Scholar]
  31. 31.
    Späth MR, Bartram MP, Palacio-Escat N, Hoyer KJR, Debes C et al. 2019. The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury. Kidney Int. 95:2333–49
     [Google Scholar]
  32. 32.
    Torres JA, Kruger SL, Broderick C, Amarlkhagva T, Agrawal S et al. 2019. Ketosis ameliorates renal cyst growth in polycystic kidney disease. Cell Metab. 30:61007–23.e5
     [Google Scholar]
  33. 33.
    Khundmiri SJ, Chen L, Lederer ED, Yang C-R, Knepper MA. 2021. Transcriptomes of major proximal tubule cell culture models. J. Am. Soc. Nephrol. 32:186–97
     [Google Scholar]
  34. 34.
    Monteil C, Leclere C, Dantzer F, Elkaz V, Fillastre JP, Morin JP. 1993. Modulation of glycolysis induction in primary cultures of rabbit kidney proximal tubule cells: the role of shaking, glucose and insulin Cell. . Biol. Int. 17:10953–60
     [Google Scholar]
  35. 35.
    Ren Q, Gliozzi ML, Rittenhouse NL, Edmunds LR, Rbaibi Y et al. 2019. Shear stress and oxygen availability drive differential changes in opossum kidney proximal tubule cell metabolism and endocytosis. Traffic 20:6448–59
     [Google Scholar]
  36. 36.
    Long KR, Shipman KE, Rbaibi Y, Menshikova EV, Ritov VB et al. 2017. Proximal tubule apical endocytosis is modulated by fluid shear stress via an mTOR-dependent pathway. Mol. Biol. Cell. 28:192508–17
     [Google Scholar]
  37. 37.
    Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ et al. 2015. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 526:7574564–68
     [Google Scholar]
  38. 38.
    Harder JL, Menon R, Otto EA, Zhou J, Eddy S et al. 2019. Organoid single cell profiling identifies a transcriptional signature of glomerular disease. JCI Insight 4:1122697
     [Google Scholar]
  39. 39.
    Cruz NM, Song X, Czerniecki SM, Gulieva RE, Churchill AJ et al. 2017. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease. Nat. Mater. 16:111112–19
     [Google Scholar]
  40. 40.
    Wang L, Xing X, Zeng X, Jackson SR, TeSlaa T et al. 2022. Spatially resolved isotope tracing reveals tissue metabolic activity. Nat. Methods 19:2223–30
     [Google Scholar]
  41. 41.
    Vanslambrouck JM, Wilson SB, Tan KS, Groenewegen E, Rudraraju R et al. 2022. Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids. Nat. Commun. 13:5943
     [Google Scholar]
  42. 42.
    Aceves JO, Heja S, Kobayashi K, Robinson SS, Miyoshi T et al. 2022. 3D proximal tubule-on-chip model derived from kidney organoids with improved drug uptake. Sci. Rep. 12:114997
     [Google Scholar]
  43. 43.
    Lin NYC, Homan KA, Robinson SS, Kolesky DB, Duarte N et al. 2019. Renal reabsorption in 3D vascularized proximal tubule models. PNAS 116:125399–5404
     [Google Scholar]
  44. 44.
    Balaban RS, Soltoff SP, Storey JM, Mandel LJ. 1980. Improved renal cortical tubule suspension: spectrophotometric study of O2 delivery. Am. J. Physiol. 238:1F50–59
     [Google Scholar]
  45. 45.
    Jensen MS, Mutsaers HAM, Tingskov SJ, Christensen M, Madsen MG et al. 2019. Activation of the prostaglandin E2 EP2 receptor attenuates renal fibrosis in unilateral ureteral obstructed mice and human kidney slices. Acta Physiol. 227:1e13291
     [Google Scholar]
  46. 46.
    Giera M, Yanes O, Siuzdak G. 2022. Metabolite discovery: biochemistry's scientific driver. Cell Metab. 34:121–34
     [Google Scholar]
  47. 47.
    Alexandrov T. 2020. Spatial metabolomics and imaging mass spectrometry in the age of artificial intelligence. Annu. Rev. Biomed. Data Sci. 3:61–87
     [Google Scholar]
  48. 48.
    Jang C, Chen L, Rabinowitz JD. 2018. Metabolomics and isotope tracing. Cell 173:4822–37
     [Google Scholar]
  49. 49.
    Buescher JM, Antoniewicz MR, Boros LG, Burgess SC, Brunengraber H et al. 2015. A roadmap for interpreting 13C metabolite labeling patterns from cells. Curr. Opin. Biotechnol. 34:189–201
     [Google Scholar]
  50. 50.
    Gewin LS. 2021. Sugar or fat? Renal tubular metabolism reviewed in health and disease. Nutrients 13:51580
     [Google Scholar]
  51. 51.
    Bhargava P, Schnellmann RG. 2017. Mitochondrial energetics in the kidney. Nat. Rev. Nephrol. 13:10629–46
     [Google Scholar]
  52. 52.
    Doke T, Susztak K. 2022. The multifaceted role of kidney tubule mitochondrial dysfunction in kidney disease development. Trends Cell Biol. 32:10841–53
     [Google Scholar]
  53. 53.
    Hui S, Cowan AJ, Zeng X, Yang L, TeSlaa T et al. 2020. Quantitative fluxomics of circulating metabolites. Cell Metab. 32:4676–88
     [Google Scholar]
  54. 54.
    Rieg T, Vallon V. 2018. Development of SGLT1 and SGLT2 inhibitors. Diabetologia 61:102079–86
     [Google Scholar]
  55. 55.
    Li Y, Nourbakhsh N, Pham H, Tham R, Zuckerman JE, Singh P. 2020. Evolution of altered tubular metabolism and mitochondrial function in sepsis-associated acute kidney injury. Am. J. Physiol. Ren. Physiol. 319:2F229–44
     [Google Scholar]
  56. 56.
    Gu M, Tan M, Zhou L, Sun X, Lu Q et al. 2022. Protein phosphatase 2Acα modulates fatty acid oxidation and glycolysis to determine tubular cell fate and kidney injury. Kidney Int. 102:2321–36
     [Google Scholar]
  57. 57.
    Smith JA, Stallons LJ, Schnellmann RG. 2014. Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury. Am. J. Physiol. Ren. Physiol. 307:4F435–44
     [Google Scholar]
  58. 58.
    Harzandi A, Lee S, Bidkhori G, Saha S, Hendry BM et al. 2021. Acute kidney injury leading to CKD is associated with a persistence of metabolic dysfunction and hypertriglyceridemia. iScience 24:2102046
     [Google Scholar]
  59. 59.
    Lan R, Geng H, Singha PK, Saikumar P, Bottinger EP et al. 2016. Mitochondrial pathology and glycolytic shift during proximal tubule atrophy after ischemic AKI. J. Am. Soc. Nephrol. 27:113356–67
     [Google Scholar]
  60. 60.
    Frank H, Gröger N, Diener M, Becker C, Braun T, Boettger T. 2008. Lactaturia and loss of sodium-dependent lactate uptake in the colon of SLC5A8-deficient mice. J. Biol. Chem. 283:3624729–37
     [Google Scholar]
  61. 61.
    Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X et al. 2017. Glucose feeds the TCA cycle via circulating lactate. Nature 551:7678115–18
     [Google Scholar]
  62. 62.
    Nielsen PM, Mariager CØ, Mølmer M, Sparding N, Genovese F et al. 2020. Hyperpolarized [1-13C] alanine production: a novel imaging biomarker of renal fibrosis. Magn. Reson. Med. 84:42063–73
     [Google Scholar]
  63. 63.
    Meyer C, Stumvoll M, Dostou J, Welle S, Haymond M, Gerich J. 2002. Renal substrate exchange and gluconeogenesis in normal postabsorptive humans. Am. J. Physiol. Endocrinol. Metab. 282:2E428–34
     [Google Scholar]
  64. 64.
    Guder WG. 1979. Stimulation of renal gluconeogenesis by angiotensin II. Biochim. Biophys. Acta 584:3507–19
     [Google Scholar]
  65. 65.
    Akhtar S, Culver SA, Siragy HM. 2021. Novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway. Sci. Rep. 11:111367
     [Google Scholar]
  66. 66.
    Legouis D, Ricksten S-E, Faivre A, Verissimo T, Gariani K et al. 2020. Altered proximal tubular cell glucose metabolism during acute kidney injury is associated with mortality. Nat. Metab. 2:8732–43
     [Google Scholar]
  67. 67.
    Verissimo T, Faivre A, Rinaldi A, Lindenmeyer M, Delitsikou V et al. 2022. Decreased renal gluconeogenesis is a hallmark of chronic kidney disease. J. Am. Soc. Nephrol. 33:4810–27
     [Google Scholar]
  68. 68.
    Kang J, Dai X-S, Yu T-B, Wen B, Yang Z-W 2005. Glycogen accumulation in renal tubules, a key morphological change in the diabetic rat kidney. Acta Diabetol. 42:2110–16
     [Google Scholar]
  69. 69.
    Nieth H, Schollmeyer P. 1966. Substrate-utilization of the human kidney. Nature 209:50291244–45
     [Google Scholar]
  70. 70.
    Kang HM, Ahn SH, Choi P, Ko Y-A, Han SH et al. 2015. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21:137–46
     [Google Scholar]
  71. 71.
    Guder WG, Wagner S, Wirthensohn G. 1986. Metabolic fuels along the nephron: pathways and intracellular mechanisms of interaction. Kidney Int. 29:141–45
     [Google Scholar]
  72. 72.
    Bobulescu IA. 2010. Renal lipid metabolism and lipotoxicity. Curr. Opin. Nephrol. Hypertens. 19:4393–402
     [Google Scholar]
  73. 73.
    Pérez-Martí A, Ramakrishnan S, Li J, Dugourd A, Molenaar MR et al. 2022. Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes. eLife 11:e74391
     [Google Scholar]
  74. 74.
    Yamamoto T, Takabatake Y, Minami S, Sakai S, Fujimura R et al. 2021. Eicosapentaenoic acid attenuates renal lipotoxicity by restoring autophagic flux. Autophagy 17:71700–13
     [Google Scholar]
  75. 75.
    Venable AH, Lee LE, Feola K, Santoyo J, Broomfield T, Huen SC. 2022. Fasting-induced HMGCS2 expression in the kidney does not contribute to circulating ketones. Am. J. Physiol. Ren. Physiol. 322:4F460–67
     [Google Scholar]
  76. 76.
    Blanco A, Blanco G 2017. Amino acid metabolism. Medical Biochemistry A Blanco, G Blanco 367–99 New York: Academic
     [Google Scholar]
  77. 77.
    Curthoys NP, Moe OW. 2014. Proximal tubule function and response to acidosis. Clin. J. Am. Soc. Nephrol. 9:91627–38
     [Google Scholar]
  78. 78.
    Chen Q, Kirk K, Shurubor YI, Zhao D, Arreguin AJ et al. 2018. Rewiring of glutamine metabolism is a bioenergetic adaptation of human cells with mitochondrial DNA mutations. Cell Metab. 27:51007–25.e5
     [Google Scholar]
  79. 79.
    Moret C, Dave MH, Schulz N, Jiang JX, Verrey F, Wagner CA. 2007. Regulation of renal amino acid transporters during metabolic acidosis. Am. J. Physiol. Ren. Physiol. 292:2F555–66
     [Google Scholar]
  80. 80.
    Liu GY, Sabatini DM. 2020. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21:4183–203
     [Google Scholar]
  81. 81.
    Grahammer F, Ramakrishnan SK, Rinschen MM, Larionov AA, Syed M et al. 2017. mTOR regulates endocytosis and nutrient transport in proximal tubular cells. J. Am. Soc. Nephrol. 28:1230–41
     [Google Scholar]
  82. 82.
    Grahammer F, Haenisch N, Steinhardt F, Sandner L, Roerden M et al. 2014. mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress. PNAS 111:27E2817–26
     [Google Scholar]
  83. 83.
    Gleixner EM, Canaud G, Hermle T, Guida MC, Kretz O et al. 2014. V-ATPase/mTOR signaling regulates megalin-mediated apical endocytosis. Cell Rep. 8:110–19
     [Google Scholar]
  84. 84.
    Li H, Thali RF, Smolak C, Gong F, Alzamora R et al. 2010. Regulation of the creatine transporter by AMP-activated protein kinase in kidney epithelial cells. Am. J. Physiol. Ren. Physiol. 299:1F167–177
     [Google Scholar]
  85. 85.
    Viollet B, Athea Y, Remi, Guigas B, Zarrinpashneh E et al. 2009. AMPK: lessons from transgenic and knockout animals. Front. Biosci. 14:19–44
     [Google Scholar]
  86. 86.
    Glosse P, Föller M. 2018. AMP-activated protein kinase (AMPK)-dependent regulation of renal transport. Int. J. Mol. Sci. 19:113481
     [Google Scholar]
  87. 87.
    Rajani R, Pastor-Soler NM, Hallows KR. 2017. Role of AMP-activated protein kinase in kidney tubular transport, metabolism, and disease. Curr. Opin. Nephrol. Hypertens. 26:5375–83
     [Google Scholar]
  88. 88.
    Lieberthal W, Zhang L, Patel VA, Levine JS. 2011. AMPK protects proximal tubular cells from stress-induced apoptosis by an ATP-independent mechanism: potential role of Akt activation. Am. J. Physiol. Ren. Physiol. 301:6F1177–92
     [Google Scholar]
  89. 89.
    Tsogbadrakh B, Ryu H, Ju KD, Lee J, Yun S et al. 2019. AICAR, an AMPK activator, protects against cisplatin-induced acute kidney injury through the JAK/STAT/SOCS pathway. Biochem. Biophys. Res. Commun. 509:3680–86
     [Google Scholar]
  90. 90.
    Declèves A-E, Zolkipli Z, Satriano J, Wang L, Nakayama T et al. 2014. Regulation of lipid accumulation by AMK-activated kinase in high fat diet-induced kidney injury. Kidney Int. 85:3611–23
     [Google Scholar]
  91. 91.
    Xiao J, Zhu S, Guan H, Zheng Y, Li F et al. 2019. AMPK alleviates high uric acid-induced Na+-K+-ATPase signaling impairment and cell injury in renal tubules. Exp. Mol. Med. 51:51–14
     [Google Scholar]
  92. 92.
    Al-bataineh MM, Gong F, Marciszyn AL, Myerburg MM, Pastor-Soler NM. 2014. Regulation of proximal tubule vacuolar H+-ATPase by PKA and AMP-activated protein kinase. Am. J. Physiol. Ren. Physiol. 306:9F981–95
     [Google Scholar]
  93. 93.
    Ohashi Y. 2021. Activation mechanisms of the VPS34 complexes. Cells 10:113124
     [Google Scholar]
  94. 94.
    Yuan H-X, Russell RC, Guan K-L. 2013. Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy 9:121983–95
     [Google Scholar]
  95. 95.
    Yoon M-S, Son K, Arauz E, Han JM, Kim S, Chen J. 2016. Leucyl-tRNA synthetase activates Vps34 in amino acid-sensing mTORC1 signaling. Cell Rep. 16:61510–17
     [Google Scholar]
  96. 96.
    Tremel S, Ohashi Y, Morado DR, Bertram J, Perisic O et al. 2021. Structural basis for VPS34 kinase activation by Rab1 and Rab5 on membranes. Nat. Commun. 12:1564
     [Google Scholar]
  97. 97.
    Ohashi Y, Tremel S, Masson GR, McGinney L, Boulanger J et al. 2020. Membrane characteristics tune activities of endosomal and autophagic human VPS34 complexes. eLife 9:e58281
     [Google Scholar]
  98. 98.
    Grieco G, Janssens V, Gaide Chevronnay HP, N'Kuli F, Van Der Smissen P et al. 2018. Vps34/PI3KC3 deletion in kidney proximal tubules impairs apical trafficking and blocks autophagic flux, causing a Fanconi-like syndrome and renal insufficiency. Sci. Rep. 8:114133
     [Google Scholar]
  99. 99.
    Rinschen MM, Harder JL, Carter-Timofte ME, Zanon Rodriguez L, Mirabelli C et al. 2022. VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney. Sci. Signal. 15:762eabo7940
     [Google Scholar]
  100. 100.
    Rajkumar P, Cha B, Yin J, Arend LJ, Păunescu TG et al. 2018. Identifying the localization and exploring a functional role for Gprc5c in the kidney. FASEB J. 32:42046–59
     [Google Scholar]
  101. 101.
    Rajkumar P, Pluznick JL. 2018. Acid-base regulation in the renal proximal tubules: using novel pH sensors to maintain homeostasis. Am. J. Physiol. Ren. Physiol. 315:5F1187–90
     [Google Scholar]
  102. 102.
    Warth R, Barrière H, Meneton P, Bloch M, Thomas J et al. 2004. Proximal renal tubular acidosis in TASK2 K+ channel-deficient mice reveals a mechanism for stabilizing bicarbonate transport. PNAS 101:218215–20
     [Google Scholar]
  103. 103.
    Yang LV, Radu CG, Roy M, Lee S, McLaughlin J et al. 2007. Vascular abnormalities in mice deficient for the G protein-coupled receptor GPR4 that functions as a pH sensor. Mol. Cell. Biol. 27:41334–47
     [Google Scholar]
  104. 104.
    Hurtado-Lorenzo A, Skinner M, El Annan J, Futai M, Sun-Wada G-H et al. 2006. V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat. Cell Biol. 8:2124–36
     [Google Scholar]
  105. 105.
    Beenken A, Cerutti G, Brasch J, Guo Y, Sheng Z et al. 2023. Structures of LRP2 reveal a molecular machine for endocytosis. Cell 186:4821–36.e13
     [Google Scholar]
  106. 106.
    Wang Y-P, Lei Q-Y. 2018. Metabolite sensing and signaling in cell metabolism. Signal Transduct. Target. Ther. 3:130
     [Google Scholar]
  107. 107.
    Tran MT, Zsengeller ZK, Berg AH, Khankin EV, Bhasin MK et al. 2016. PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 531:7595528–32
     [Google Scholar]
  108. 108.
    Khamissi FZ, Ning L, Kefaloyianni E, Dun H, Arthanarisami A et al. 2022. Identification of kidney injury released circulating osteopontin as causal agent of respiratory failure. Sci. Adv. 8:8eabm5900
     [Google Scholar]
  109. 109.
    Ngo D, Wen D, Gao Y, Keyes MJ, Drury ER et al. 2020. Circulating testican-2 is a podocyte-derived marker of kidney health. PNAS 117:4025026–35
     [Google Scholar]
  110. 110.
    Solagna F, Tezze C, Lindenmeyer MT, Lu S, Wu G et al. 2021. Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs. J. Clin. Investig. 131:11e135821
     [Google Scholar]
  111. 111.
    Jang C, Hui S, Zeng X, Cowan AJ, Wang L et al. 2019. Metabolite exchange between mammalian organs quantified in pigs. Cell Metab. 30:3594–606
     [Google Scholar]
  112. 112.
    Rhee EP, Clish CB, Ghorbani A, Larson MG, Elmariah S et al. 2013. A combined epidemiologic and metabolomic approach improves CKD prediction. J. Am. Soc. Nephrol. 24:81330–38
     [Google Scholar]
  113. 113.
    Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA et al. 2009. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. PNAS 106:103698–3703
     [Google Scholar]
  114. 114.
    Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A et al. 2013. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. PNAS 110:114410–15
     [Google Scholar]
  115. 115.
    Lobel L, Cao YG, Fenn K, Glickman JN, Garrett WS. 2020. Diet posttranslationally modifies the mouse gut microbial proteome to modulate renal function. Science 369:65101518–24
     [Google Scholar]
  116. 116.
    Tanaka H, Sirich TL, Plummer NS, Weaver DS, Meyer TW. 2015. An enlarged profile of uremic solutes. PLOS ONE 10:8e0135657
     [Google Scholar]
  117. 117.
    Ravid JD, Kamel MH, Chitalia VC. 2021. Uraemic solutes as therapeutic targets in CKD-associated cardiovascular disease. Nat. Rev. Nephrol. 17:6402–16
     [Google Scholar]
  118. 118.
    Gryp T, Paepe KD, Vanholder R, Kerckhof F-M, Biesen WV et al. 2020. Gut microbiota generation of protein-bound uremic toxins and related metabolites is not altered at different stages of chronic kidney disease. Kidney Int. 97:61230–42
     [Google Scholar]
  119. 119.
    Nigam SK. 2018. The SLC22 transporter family: a paradigm for the impact of drug transporters on metabolic pathways, signaling, and disease. Annu. Rev. Pharmacol. Toxicol. 58:663–87
     [Google Scholar]
  120. 120.
    Yee SW, Giacomini KM. 2021. Emerging roles of the human solute carrier 22 family. Drug Metab. Dispos. Biol. Fate Chem. 50:91193–1210
     [Google Scholar]
  121. 121.
    Granados JC, Richelle A, Gutierrez JM, Zhang P, Zhang X et al. 2021. Coordinate regulation of systemic and kidney tryptophan metabolism by the drug transporters OAT1 and OAT3. J. Biol. Chem. 296:100575
     [Google Scholar]
  122. 122.
    Granados JC, Nigam AK, Bush KT, Jamshidi N, Nigam SK. 2021. A key role for the transporter OAT1 in systemic lipid metabolism. J. Biol. Chem. 296:100603
     [Google Scholar]
  123. 123.
    Jansen J, Jansen K, Neven E, Poesen R, Othman A et al. 2019. Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion. PNAS 116:3216105–10
     [Google Scholar]
  124. 124.
    Tian Z, Liang M. 2021. Renal metabolism and hypertension. Nat. Commun. 12:1963
     [Google Scholar]
  125. 125.
    Warren HR, Evangelou E, Cabrera CP, Gao H, Ren M et al. 2017. Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat. Genet. 49:3403–15
     [Google Scholar]
  126. 126.
    Cheng Y, Song H, Pan X, Xue H, Wan Y et al. 2018. Urinary metabolites associated with blood pressure on a low- or high-sodium diet. Theranostics 8:61468–80
     [Google Scholar]
  127. 127.
    Mell B, Jala VR, Mathew AV, Byun J, Waghulde H et al. 2015. Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol. Genom. 47:6187–97
     [Google Scholar]
  128. 128.
    Chakraborty S, Galla S, Cheng X, Yeo J-Y, Mell B et al. 2018. Salt-responsive metabolite, β-hydroxybutyrate, attenuates hypertension. Cell Rep. 25:3677–89
     [Google Scholar]
  129. 129.
    Chakraborty S, Mandal J, Yang T, Cheng X, Yeo J-Y et al. 2020. Metabolites and hypertension: insights into hypertension as a metabolic disorder: 2019 Harriet Dustan Award. Hypertension 75:61386–96
     [Google Scholar]
  130. 130.
    Rinschen MM, Palygin O, Guijas C, Palermo A, Palacio-Escat N et al. 2019. Metabolic rewiring of the hypertensive kidney. Sci. Signal. 12:611eaax9760
     [Google Scholar]
  131. 131.
    McMahon GM, Hwang S-J, Clish CB, Tin A, Yang Q et al. 2017. Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease. Kidney Int. 91:61426–35
     [Google Scholar]
  132. 132.
    Li Y, Sekula P, Wuttke M, Wahrheit J, Hausknecht B et al. 2018. Genome-wide association studies of metabolites in patients with CKD identify multiple loci and illuminate tubular transport mechanisms. J. Am. Soc. Nephrol. 29:51513–24
     [Google Scholar]
  133. 133.
    Rebholz CM, Lichtenstein AH, Zheng Z, Appel LJ, Coresh J. 2018. Serum untargeted metabolomic profile of the Dietary Approaches to Stop Hypertension (DASH) dietary pattern. Am. J. Clin. Nutr. 108:2243–55
     [Google Scholar]
  134. 134.
    Rinschen MM, Palygin O, El-Meanawy A, Domingo-Almenara X, Palermo A et al. 2022. Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension. Nat. Commun. 13:4099
     [Google Scholar]
  135. 135.
    Wang TJ, Ngo D, Psychogios N, Dejam A, Larson MG et al. 2013. 2-Aminoadipic acid is a biomarker for diabetes risk. J. Clin. Investig. 123:104309–17
     [Google Scholar]
  136. 136.
    Kirabo A, Fontana V, de Faria APC, Loperena R, Galindo CL et al. 2014. DC isoketal-modified proteins activate T cells and promote hypertension. J. Clin. Investig. 124:104642–56
     [Google Scholar]
  137. 137.
    Thelle K, Christensen EI, Vorum H, Ørskov H, Birn H. 2006. Characterization of proteinuria and tubular protein uptake in a new model of oral l-lysine administration in rats. Kidney Int. 69:81333–40
     [Google Scholar]
  138. 138.
    Baker SA, Rutter J. 2023. Metabolites as signalling molecules. Nat. Rev. Mol. Cell Biol. 24:355–74
     [Google Scholar]
  139. 139.
    Stroeve JHM, van Wietmarschen H, Kremer BHA, van Ommen B, Wopereis S. 2015. Phenotypic flexibility as a measure of health: the optimal nutritional stress response test. Genes Nutr. 10:313
     [Google Scholar]
/content/journals/10.1146/annurev-physiol-042222-024724
Loading
Metabolic Rewiring and Communication: An Integrative View of Kidney Proximal Tubule Function
Annual Review of Physiology 86, 405 (2024); https://doi.org/10.1146/annurev-physiol-042222-024724
/content/journals/10.1146/annurev-physiol-042222-024724
/content/journals/10.1146/annurev-physiol-042222-024724
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error