Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The pathobiology of polycystic kidney disease from a metabolic viewpoint

Nature Reviews Nephrology volume 15, pages 735–749 (2019)Cite this article

Subjects

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) affects an estimated 1 in 1,000 people and slowly progresses to end-stage renal disease (ESRD) in about half of these individuals. Tolvaptan, a vasopressin 2 receptor blocker, has been approved by regulatory authorities in many countries as a therapy to slow cyst growth, but additional treatments that target dysregulated signalling pathways in cystic kidney and liver are needed. Metabolic reprogramming is a prominent feature of cystic cells and a potentially important contributor to the pathophysiology of ADPKD. A number of pathways previously implicated in the pathogenesis of the disease, such as dysregulated mTOR and primary ciliary signalling, have roles in metabolic regulation and may exert their effects through this mechanism. Some of these pathways are amenable to manipulation through dietary modifications or drug therapies. Studies suggest that polycystin-1 and polycystin-2, which are encoded by PKD1 and PKD2, respectively (the genes that are mutated in >99% of patients with ADPKD), may in part affect cellular metabolism through direct effects on mitochondrial function. Mitochondrial dysfunction could alter the redox state and cellular levels of acetyl-CoA, resulting in altered histone acetylation, gene expression, cytoskeletal architecture and response to cellular stress, and in an immunological response that further promotes cyst growth and fibrosis.

Key points

  • Several pathways that have been implicated in the pathogenesis of polycystic kidney disease (PKD) have metabolic functions and increasing evidence suggests that altered cellular metabolism is an intrinsic component of the disease.

  • Dysregulation of cyclic AMP signalling is thought to be a driver of cystogenesis; the cAMP-targeting drug tolvaptan has now been approved for the treatment of autosomal dominant PKD (ADPKD) in patients who are at high risk of progression to end-stage renal disease.

  • Multiple metabolic pathways (fatty acid oxidation (FAO), glycolysis and glutamine metabolism) have also been reported to be dysregulated in PKD models; evidence suggests that polycystin-1 (PC1) might regulate mTOR activity.

  • Data from animal studies suggest that dietary modifications that alter metabolism such as protein, fat and/or calorie restriction could be reasonable therapeutic options in patients with ADPKD.

  • Pkd1-knockout cells have abnormal mitochondrial morphology and impaired FAO; a C-terminal fragment of PC1 that traffics to mitochondria may regulate their function and morphology.

  • Understanding the interplay between dysregulation of cellular metabolism and cystogenesis is likely to uncover pathways that can be directly modulated to treat PKD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cyclic AMP signalling in PKD.
Fig. 2: Model of metabolic dysfunction in PKD.
Fig. 3: Intersecting pathways control ciliary and mitochondrial function.

Similar content being viewed by others

References

  1. Torres, V., Harris, P. & Pirson, Y. Autosomal dominant polycystic kidney disease. Lancet 369, 1287–1301 (2007).

    PubMed  Google Scholar 

  2. Spithoven, E. M. et al. Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease. Kidney Int. 86, 1244–1252 (2014).

    PubMed  Google Scholar 

  3. Rodriguez-Osorio, L., Vanessa Perez-Gomez, M. & Ortiz, A. Decreasing incidence of renal replacement therapy over time at the critical 50-59-year age range suggests a role for nephroprotective therapy in ADPKD. Kidney Int. 88, 194 (2015).

    CAS  PubMed  Google Scholar 

  4. Schrier, R. W. et al. Blood pressure in early autosomal dominant polycystic kidney disease. N. Engl. J. Med. 371, 2255–2266 (2014).

    PubMed  PubMed Central  Google Scholar 

  5. Torres, V. E. et al. Angiotensin blockade in late autosomal dominant polycystic kidney disease. N. Engl. J. Med. 371, 2267–2276 (2014).

    PubMed  PubMed Central  Google Scholar 

  6. Torres, V. E. et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 367, 2407-2418 (2012).

    CAS  Google Scholar 

  7. Torres, V. E. et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N. Engl. J. Med. 377, 1930–1942 (2017).

    CAS  PubMed  Google Scholar 

  8. Lanktree, M. B. & Chapman, A. B. New treatment paradigms for ADPKD: moving towards precision medicine. Nat. Rev. Nephrol. 13, 750–768 (2017).

    CAS  PubMed  Google Scholar 

  9. Kalantar-Zadeh, K. & Fouque, D. Nutritional management of chronic kidney disease. N. Engl. J. Med. 377, 1765–1776 (2017).

    CAS  PubMed  Google Scholar 

  10. Klahr, S. et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N. Engl. J. Med. 330, 877–884 (1994).

    CAS  PubMed  Google Scholar 

  11. Klahr, S. et al. Dietary protein restriction, blood pressure control, and the progression of polycystic kidney disease. Modification of Diet in Renal Disease Study Group. J. Am. Soc. Nephrol. 5, 2037–2047 (1995).

    CAS  PubMed  Google Scholar 

  12. Warner, G. et al. Food restriction ameliorates the development of polycystic kidney disease. J. Am. Soc. Nephrol. 27, 1437–1447 (2016).

    CAS  PubMed  Google Scholar 

  13. Padovano, V., Podrini, C., Boletta, A. & Caplan, M. J. Metabolism and mitochondria in polycystic kidney disease research and therapy. Nat. Rev. Nephrol. 14, 678–687 (2018).

    CAS  PubMed  Google Scholar 

  14. Cooper, D. M. Regulation and organization of adenylyl cyclases and cAMP. Biochem. J. 375, 517–529 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Pinto, C. S., Reif, G. A., Nivens, E., White, C. & Wallace, D. P. Calmodulin-sensitive adenylyl cyclases mediate AVP-dependent cAMP production and Cl− secretion by human autosomal dominant polycystic kidney cells. Am. J. Physiol. Ren. Physiol. 303, F1412–F1424 (2012).

    CAS  Google Scholar 

  16. Litvin, T. N., Kamenetsky, M., Zarifyan, A., Buck, J. & Levin, L. R. Kinetic properties of "soluble" adenylyl cyclase. Synergism between calcium and bicarbonate. J. Biol. Chem. 278, 15922–15926 (2003).

    CAS  PubMed  Google Scholar 

  17. Sassone-Corsi, P. The cyclic AMP pathway. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a011148 (2012).

    PubMed  PubMed Central  Google Scholar 

  18. Metrich, M. et al. Epac activation induces histone deacetylase nuclear export via a Ras-dependent signalling pathway. Cell Signal. 22, 1459–1468 (2010).

    CAS  PubMed  Google Scholar 

  19. Kaupp, U. B. & Seifert, R. Cyclic nucleotide-gated ion channels. Physiol. Rev. 82, 769–824 (2002).

    CAS  PubMed  Google Scholar 

  20. Mangoo-Karim, R. et al. Renal epithelial fluid secretion and cyst growth: the role of cyclic AMP. FASEB J. 3, 2629–2632 (1989).

    CAS  PubMed  Google Scholar 

  21. Yamaguchi, T., Nagao, S., Kasahara, M., Takahashi, H. & Grantham, J. J. Renal accumulation and excretion of cyclic adenosine monophosphate in a murine model of slowly progressive polycystic kidney disease. Am. J. Kidney Dis. 30, 703–709 (1997).

    CAS  PubMed  Google Scholar 

  22. Davidow, C. J., Maser, R. L., Rome, L. A., Calvet, J. P. & Grantham, J. J. The cystic fibrosis transmembrane conductance regulator mediates transepithelial fluid secretion by human autosomal dominant polycystic kidney disease epithelium in vitro. Kidney Int. 50, 208–218 (1996).

    CAS  PubMed  Google Scholar 

  23. Hanaoka, K. & Guggino, W. B. cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells. J. Am. Soc. Nephrol. 11, 1179–1187 (2000).

    CAS  PubMed  Google Scholar 

  24. Wallace, D. P. Cyclic AMP-mediated cyst expansion. Biochim. Biophys. Acta 1812, 1291–1300 (2011).

    CAS  PubMed  Google Scholar 

  25. Tanner, G. A. & Tanner, J. A. Chronic caffeine consumption exacerbates hypertension in rats with polycystic kidney disease. Am. J. Kidney Dis. 38, 1089–1095 (2001).

    CAS  PubMed  Google Scholar 

  26. Gattone, V. H., Wang, X., Harris, P. C. & Torres, V. E. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat. Med. 9, 1323–1326 (2003).

    CAS  PubMed  Google Scholar 

  27. Meijer, E. et al. Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: optimal timing and dosing of the drug. Nephrol. Dial. Transpl. 26, 2445–2453 (2011).

    CAS  Google Scholar 

  28. Hopp, K. et al. Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J. Am. Soc. Nephrol. 26, 39–47 (2015).

    CAS  PubMed  Google Scholar 

  29. Torres, V. et al. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat. Med. 10, 363–364 (2004).

    CAS  PubMed  Google Scholar 

  30. Wang, X., Wu, Y., Ward, C. J., Harris, P. C. & Torres, V. E. Vasopressin directly regulates cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 19, 102–108 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rees, S. et al. Adenylyl cyclase 6 deficiency ameliorates polycystic kidney disease. J. Am. Soc. Nephrol. 25, 232–237 (2014).

    CAS  PubMed  Google Scholar 

  32. Ye, H. et al. Modulation of polycystic kidney disease severity by phosphodiesterase 1 and 3 subfamilies. J. Am. Soc. Nephrol. 27, 1312–1320 (2016).

    CAS  PubMed  Google Scholar 

  33. Zittema, D. et al. Dose-titrated vasopressin V2 receptor antagonist improves renoprotection in a mouse model for autosomal dominant polycystic kidney disease. Am. J. Nephrol. 44, 194–203 (2016).

    CAS  PubMed  Google Scholar 

  34. Roix, J. & Saha, S. TNF-α blockade is ineffective in animal models of established polycystic kidney disease. BMC Nephrol. 14, 233 (2013).

    PubMed  PubMed Central  Google Scholar 

  35. Torres, V. E. et al. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 trial. Nephrol. Dial. Transpl. 33, 477–489 (2018).

    CAS  Google Scholar 

  36. FDA. Risk Evaluation Mitigation Strategy (REMS) Document. JYNARQUE (tolvaptan) REMS program. FDA https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/204441Orig1s000REMS.pdf (2018).

  37. Edwards, M. E. et al. Long-term administration of tolvaptan in autosomal dominant polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 13, 1153–1161 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ruggenenti, P. et al. Safety and efficacy of long-acting somatostatin treatment in autosomal-dominant polycystic kidney disease. Kidney Int. 68, 206–216 (2005).

    CAS  PubMed  Google Scholar 

  39. Caroli, A. et al. Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet 382, 1485–1495 (2013).

    CAS  PubMed  Google Scholar 

  40. Perico, N. et al. Octreotide-LAR in later-stage autosomal dominant polycystic kidney disease (ALADIN 2): a randomized, double-blind, placebo-controlled, multicenter trial. PLOS Med. 16, e1002777 (2019).

    PubMed  PubMed Central  Google Scholar 

  41. Meijer, E. et al. Effect of lanreotide on kidney function in patients with autosomal dominant polycystic kidney disease: the DIPAK 1 randomized clinical trial. JAMA 320, 2010–2019 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Nagao, S. et al. Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J. Am. Soc. Nephrol. 17, 2220–2227 (2006).

    CAS  PubMed  Google Scholar 

  43. Hopp, K. et al. Effects of hydration in rats and mice with polycystic kidney disease. Am. J. Physiol. Renal Physiol. 308, F261–F266 (2015).

    CAS  PubMed  Google Scholar 

  44. Higashihara, E. et al. Does increased water intake prevent disease progression in autosomal dominant polycystic kidney disease? Nephrol. Dial. Transpl. 29, 1710–1719 (2014).

    CAS  Google Scholar 

  45. Wong, A. T. Y. et al. Randomised controlled trial to determine the efficacy and safety of prescribed water intake to prevent kidney failure due to autosomal dominant polycystic kidney disease (PREVENT-ADPKD). BMJ Open 8, e018794 (2018).

    PubMed  PubMed Central  Google Scholar 

  46. El-Damanawi, R. et al. Randomised controlled trial of high versus ad libitum water intake in patients with autosomal dominant polycystic kidney disease: rationale and design of the DRINK feasibility trial. BMJ Open 8, e022859 (2018).

    PubMed  PubMed Central  Google Scholar 

  47. Belibi, F. A. et al. The effect of caffeine on renal epithelial cells from patients with autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 13, 2723–2729 (2002).

    CAS  PubMed  Google Scholar 

  48. Vendramini, L. C., Nishiura, J. L., Baxmann, A. C. & Heilberg, I. P. Caffeine intake by patients with autosomal dominant polycystic kidney disease. Braz. J. Med. Biol. Res. 45, 834–840 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Girardat-Rotar, L., Puhan, M. A., Braun, J. & Serra, A. L. Long-term effect of coffee consumption on autosomal dominant polycystic kidneys disease progression: results from the Suisse ADPKD, a prospective longitudinal cohort study. J. Nephrol. 31, 87–94 (2017).

    PubMed  PubMed Central  Google Scholar 

  50. Armstrong, L. E. et al. Fluid, electrolyte, and renal indices of hydration during 11 days of controlled caffeine consumption. Int. J. Sport Nutr. Exerc. Metab. 15, 252–265 (2005).

    CAS  PubMed  Google Scholar 

  51. Clayton, J. A. & Collins, F. S. Policy: NIH to balance sex in cell and animal studies. Nature 509, 282–283 (2014).

    PubMed  PubMed Central  Google Scholar 

  52. Clayton, J. A. Studying both sexes: a guiding principle for biomedicine. FASEB J. 30, 519–524 (2016).

    CAS  PubMed  Google Scholar 

  53. Patsopoulos, N. A., Tatsioni, A. & Ioannidis, J. P. Claims of sex differences: an empirical assessment in genetic associations. JAMA 298, 880–893 (2007).

    CAS  PubMed  Google Scholar 

  54. Ober, C., Loisel, D. A. & Gilad, Y. Sex-specific genetic architecture of human disease. Nat. Rev. Genet. 9, 911–922 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu, J. et al. Sex differences in vasopressin V2 receptor expression and vasopressin-induced antidiuresis. Am. J. Physiol. Ren. Physiol. 300, F433–F440 (2011).

    CAS  Google Scholar 

  56. Ljubojevic, M. et al. Rat renal cortical OAT1 and OAT3 exhibit gender differences determined by both androgen stimulation and estrogen inhibition. Am. J. Physiol. Renal Physiol. 287, F124–F138 (2004).

    CAS  PubMed  Google Scholar 

  57. Veiras, L. C. et al. Sexual dimorphic pattern of renal transporters and electrolyte homeostasis. J. Am. Soc. Nephrol. 28, 3504–3517 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Menezes, L. F., Lin, C. C., Zhou, F. & Germino, G. G. Fatty acid oxidation is impaired in an orthologous mouse model of autosomal dominant polycystic kidney disease. EBioMedicine 5, 183–192 (2016).

    PubMed  PubMed Central  Google Scholar 

  59. Müller, V. et al. Sexual dimorphism in renal ischemia-reperfusion injury in rats: possible role of endothelin. Kidney Int. 62, 1364–1371 (2002).

    PubMed  Google Scholar 

  60. Park, K. M., Kim, J. I., Ahn, Y., Bonventre, A. J. & Bonventre, J. V. Testosterone is responsible for enhanced susceptibility of males to ischemic renal injury. J. Biol. Chem. 279, 52282–52292 (2004).

    CAS  PubMed  Google Scholar 

  61. Soljancic, A. et al. Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury. Am. J. Physiol. Regul. Integr. Comp. Physiol. 304, R951–R958 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Tanaka, R. et al. Sex differences in ischemia/reperfusion-induced acute kidney injury are dependent on the renal sympathetic nervous system. Eur. J. Pharmacol. 714, 397–404 (2013).

    CAS  PubMed  Google Scholar 

  63. Neugarten, J. & Golestaneh, L. Gender and the prevalence and progression of renal disease. Adv. Chronic Kidney Dis. 20, 390–395 (2013).

    PubMed  Google Scholar 

  64. Neugarten, J., Acharya, A. & Silbiger, S. R. Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. J. Am. Soc. Nephrol. 11, 319–329 (2000).

    CAS  PubMed  Google Scholar 

  65. Qian, F., Watnick, T. J., Onuchic, L. F. & Germino, G. G. The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87, 979–987 (1996).

    CAS  PubMed  Google Scholar 

  66. Reed, B. Y. et al. Variation in age at ESRD in autosomal dominant polycystic kidney disease. Am. J. Kidney Dis. 51, 173–183 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Magistroni, R. et al. Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 14, 1164–1174 (2003).

    PubMed  Google Scholar 

  68. Gretz, N. et al. Gender-dependent disease severity in autosomal polycystic kidney disease of rats. Kidney Int. 48, 496–500 (1995).

    CAS  PubMed  Google Scholar 

  69. Cowley, B. D., Grantham, J. J., Muessel, M. J., Kraybill, A. L. & Gattone, V. H. Modification of disease progression in rats with inherited polycystic kidney disease. Am. J. Kidney Dis. 27, 865–879 (1996).

    PubMed  Google Scholar 

  70. Nagao, S. et al. Androgen receptor pathway in rats with autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 16, 2052–2062 (2005).

    CAS  PubMed  Google Scholar 

  71. Stringer, K. D. et al. Gender hormones and the progression of experimental polycystic kidney disease. Kidney Int. 68, 1729–1739 (2005).

    CAS  PubMed  Google Scholar 

  72. Anderson, S. et al. 2-Hydroxyestradiol slows progression of experimental polycystic kidney disease. Am. J. Physiol. Renal Physiol. 302, F636–F645 (2012).

    CAS  PubMed  Google Scholar 

  73. Lager, D. J., Qian, Q., Bengal, R. J., Ishibashi, M. & Torres, V. E. The pck rat: a new model that resembles human autosomal dominant polycystic kidney and liver disease. Kidney Int. 59, 126–136 (2001).

    CAS  PubMed  Google Scholar 

  74. Smith, L. A. et al. Development of polycystic kidney disease in juvenile cystic kidney mice: insights into pathogenesis, ciliary abnormalities, and common features with human disease. J. Am. Soc. Nephrol. 17, 2821–2831 (2006).

    CAS  PubMed  Google Scholar 

  75. Mauvais-Jarvis, F., Arnold, A. P. & Reue, K. A guide for the design of pre-clinical studies on sex differences in metabolism. Cell Metab. 25, 1216–1230 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Ronen, D. & Benvenisty, N. Sex-dependent gene expression in human pluripotent stem cells. Cell Rep. 8, 923–932 (2014).

    CAS  PubMed  Google Scholar 

  77. 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).

    CAS  PubMed  Google Scholar 

  78. Piontek, K., Menezes, L., Garcia-Gonzalez, M., Huso, D. & Germino, G. A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nat. Med. 13, 1490–1495 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Menezes, L. F. et al. Network analysis of a Pkd1-mouse model of autosomal dominant polycystic kidney disease identifies HNF4α as a disease modifier. PLoS Genet. 8, e1003053 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Louet, J. F., Hayhurst, G., Gonzalez, F. J., Girard, J. & Decaux, J. F. The coactivator PGC-1 is involved in the regulation of the liver carnitine palmitoyltransferase I gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB). J. Biol. Chem. 277, 37991–38000 (2002).

    CAS  PubMed  Google Scholar 

  81. Allen, E. et al. Loss of polycystin-1 or polycystin-2 results in dysregulated apolipoprotein expression in murine tissues via alterations in nuclear hormone receptors. Hum. Mol. Genet. 15, 11–21 (2006).

    CAS  PubMed  Google Scholar 

  82. Garcia-Gonzalez, M. A. et al. Pkd1 and Pkd2 are required for normal placental development. PLOS ONE 5, e12821 (2010).

    PubMed  PubMed Central  Google Scholar 

  83. Rowe, I. et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat. Med. 19, 488–493 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Chiaravalli, M. et al. 2-Deoxy-d-glucose ameliorates PKD progression. J. Am. Soc. Nephrol. 27, 1958–1969 (2016).

    CAS  PubMed  Google Scholar 

  85. Izreig, S. et al. The miR-17 approximately 92 microRNA cluster is a global regulator of tumor metabolism. Cell Rep. 16, 1915–1928 (2016).

    CAS  PubMed  Google Scholar 

  86. Hajarnis, S. et al. microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism. Nat. Commun. 8, 14395 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Bougarne, N. et al. Molecular actions of PPARalpha in lipid metabolism and inflammation. Endocr. Rev. 39, 760–802 (2018).

    PubMed  Google Scholar 

  88. Lakhia, R. et al. PPARalpha agonist fenofibrate enhances fatty acid β-oxidation and attenuates polycystic kidney and liver disease in mice. Am. J. Physiol. Renal Physiol. 314, F122–F131 (2018).

    PubMed  Google Scholar 

  89. Weidemann, M. J. & Krebs, H. A. The fuel of respiration of rat kidney cortex. Biochem. J. 112, 149–166 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Tran, M. T. et al. PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature 531, 528–532 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Lin, C. C. et al. A cleavage product of polycystin-1 is a mitochondrial matrix protein that affects mitochondria morphology and function when heterologously expressed. Sci. Rep. 8, 2743 (2018).

    PubMed  PubMed Central  Google Scholar 

  92. Outeda, P. et al. Polycystin signaling is required for directed endothelial cell migration and lymphatic development. Cell Rep. 7, 634–644 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192–197 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Flowers, E. M. et al. Lkb1 deficiency confers glutamine dependency in polycystic kidney disease. Nat. Commun. 9, 814 (2018).

    PubMed  PubMed Central  Google Scholar 

  95. Podrini, C. et al. Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways. Commun. Biol. 1, 194 (2018).

    PubMed  PubMed Central  Google Scholar 

  96. Zhang, J. et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 56, 205–218 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Soomro, I. et al. Glutamine metabolism via glutaminase 1 in autosomal-dominant polycystic kidney disease. Nephrol. Dial. Transpl. 33, 1343–1353 (2018).

    CAS  Google Scholar 

  98. Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Wilson, G. N. et al. Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy. Am. J. Med. Genet. 32, 395–401 (1989).

    CAS  PubMed  Google Scholar 

  100. Wilson, G. N. What is Zellweger syndrome? J. Pediatr. 109, 398 (1986).

    CAS  PubMed  Google Scholar 

  101. Seeger-Nukpezah, T., Geynisman, D. M., Nikonova, A. S., Benzing, T. & Golemis, E. A. The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease. Nat. Rev. Nephrol. 11, 515–534 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Luengo, A., Gui, D. Y. & Vander Heiden, M. G. Targeting metabolism for cancer therapy. Cell Chem. Biol. 24, 1161–1180 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Courtney, K. D. et al. Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo. Cell Metab. 28, 793–800 e792 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Sborov, D. W., Haverkos, B. M. & Harris, P. J. Investigational cancer drugs targeting cell metabolism in clinical development. Expert. Opin. Investig. Drugs 24, 79–94 (2015).

    CAS  PubMed  Google Scholar 

  106. Pascual, G., Dominguez, D. & Benitah, S. A. The contributions of cancer cell metabolism to metastasis. Dis. Model. Mech. 11, dmm032920 (2018).

  107. Albert, V. & Hall, M. N. mTOR signaling in cellular and organismal energetics. Curr. Opin. Cell Biol. 33, 55–66 (2015).

    CAS  PubMed  Google Scholar 

  108. Fantus, D., Rogers, N. M., Grahammer, F., Huber, T. B. & Thomson, A. W. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat. Rev. Nephrol. 12, 587–609 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Henske, E. P., Jozwiak, S., Kingswood, J. C., Sampson, J. R. & Thiele, E. A. Tuberous sclerosis complex. Nat. Rev. Dis. Prim. 2, 16035 (2016).

    PubMed  Google Scholar 

  110. Brook-Carter, P. T. et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease – a contiguous gene syndrome. Nat. Genet. 8, 328–332 (1994).

    CAS  PubMed  Google Scholar 

  111. Shillingford, J. et al. The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl. Acad. Sci. USA 103, 5466–5471 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Shillingford, J., Piontek, K., Germino, G. & Weimbs, T. Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J. Am. Soc. Nephrol. 21, 489–497 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Pema, M. et al. mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex. Nat. Commun. 7, 10786 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Morita, M. et al. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab. 18, 698–711 (2013).

    CAS  PubMed  Google Scholar 

  117. Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).

    PubMed  PubMed Central  Google Scholar 

  118. Thoreen, C. C. et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Larsson, O. et al. Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc. Natl. Acad. Sci. USA 109, 8977–8982 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Hallows, K. R., McCane, J. E., Kemp, B. E., Witters, L. A. & Foskett, J. K. Regulation of channel gating by AMP-activated protein kinase modulates cystic fibrosis transmembrane conductance regulator activity in lung submucosal cells. J. Biol. Chem. 278, 998–1004 (2003).

    CAS  PubMed  Google Scholar 

  121. Takiar, V. et al. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc. Natl. Acad. Sci. USA 108, 2462–2467 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Seliger, S. L. et al. A randomized clinical trial of metformin to treat autosomal dominant polycystic kidney disease. Am. J. Nephrol. 47, 352–360 (2018).

    CAS  PubMed  Google Scholar 

  123. Serra, A. L. et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 820–829 (2010).

    CAS  PubMed  Google Scholar 

  124. Walz, G. et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 830–840 (2010).

    CAS  PubMed  Google Scholar 

  125. Canaud, G. et al. Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level? Am. J. Transpl. 10, 1701–1706 (2010).

    CAS  Google Scholar 

  126. Jain, N. & Reilly, R. F. Effects of dietary interventions on incidence and progression of CKD. Nat. Rev. Nephrol. 10, 712–724 (2014).

    CAS  PubMed  Google Scholar 

  127. Tomobe, K. et al. Early dietary protein restriction slows disease progression and lengthens survival in mice with polycystic kidney disease. J. Am. Soc. Nephrol. 5, 1355–1360 (1994).

    CAS  PubMed  Google Scholar 

  128. Ogborn, M. R. & Sareen, S. Amelioration of polycystic kidney disease by modification of dietary protein intake in the rat. J. Am. Soc. Nephrol. 6, 1649–1654 (1995).

    CAS  PubMed  Google Scholar 

  129. Laeger, T. et al. FGF21 is an endocrine signal of protein restriction. J. Clin. Invest. 124, 3913–3922 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Aukema, H. M., Housini, I. & Rawling, J. M. Dietary soy protein effects on inherited polycystic kidney disease are influenced by gender and protein level. J. Am. Soc. Nephrol. 10, 300–308 (1999).

    CAS  PubMed  Google Scholar 

  131. Ogborn, M. R., Nitschmann, E., Weiler, H. A. & Bankovic-Calic, N. Modification of polycystic kidney disease and fatty acid status by soy protein diet. Kidney Int. 57, 159–166 (2000).

    CAS  PubMed  Google Scholar 

  132. Aukema, H. M. & Housini, I. Dietary soy protein effects on disease and IGF-I in male and female Han:SPRD-cy rats. Kidney Int. 59, 52–61 (2001).

    CAS  PubMed  Google Scholar 

  133. Jayapalan, S., Saboorian, M. H., Edmunds, J. W. & Aukema, H. M. High dietary fat intake increases renal cyst disease progression in Han:SPRD-cy rats. J. Nutr. 130, 2356–2360 (2000).

    CAS  PubMed  Google Scholar 

  134. Mattison, J. A. et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489, 318–321 (2012).

    CAS  PubMed  Google Scholar 

  135. Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Martin, C. K. et al. Effect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy nonobese adults: the CALERIE 2 randomized clinical trial. JAMA Intern. Med. 176, 743–752 (2016).

    PubMed  PubMed Central  Google Scholar 

  137. Wang, Y. Molecular links between caloric restriction and Sir2/SIRT1 activation. Diabetes Metab. J. 38, 321–329 (2014).

    PubMed  PubMed Central  Google Scholar 

  138. Zhou, X. et al. Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. J. Clin. Invest. 123, 3084–3098 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. US Department of Health and Human Services. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03342742 (2018).

  140. Ishimoto, Y. et al. Mitochondrial abnormality facilitates cyst formation in autosomal dominant polycystic kidney disease. Mol. Cell Biol. https://doi.org/10.1128/MCB.00337-17 (2017).

  141. Kuo, I. Y. et al. Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2. Sci. Signal. 12, eaat7397 (2019).

    PubMed  PubMed Central  Google Scholar 

  142. Padovano, V. et al. The polycystins are modulated by cellular oxygen-sensing pathways and regulate mitochondrial function. Mol. Biol. Cell 28, 261–269 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Zhdanov, A. V., Okkelman, I. A., Collins, F. W., Melgar, S. & Papkovsky, D. B. A novel effect of DMOG on cell metabolism: direct inhibition of mitochondrial function precedes HIF target gene expression. Biochim. Biophys. Acta 1847, 1254–1266 (2015).

    CAS  PubMed  Google Scholar 

  144. Fedeles, S. V. et al. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat. Genet. 43, 639–647 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Chandel, N. S. Mitochondria as signaling organelles. BMC Biol. 12, 34 (2014).

    PubMed  PubMed Central  Google Scholar 

  146. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Wong, B. W. et al. The role of fatty acid β-oxidation in lymphangiogenesis. Nature 542, 49–54 (2017).

    CAS  PubMed  Google Scholar 

  149. Ghesquiere, B., Wong, B. W., Kuchnio, A. & Carmeliet, P. Metabolism of stromal and immune cells in health and disease. Nature 511, 167–176 (2014).

    CAS  PubMed  Google Scholar 

  150. Friedman, J. R. & Nunnari, J. Mitochondrial form and function. Nature 505, 335–343 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Gallegos, L. L. et al. A protein interaction map for cell-cell adhesion regulators identifies DUSP23 as a novel phosphatase for β-catenin. Sci. Rep. 6, 27114 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Sing, A. et al. The atypical cadherin fat directly regulates mitochondrial function and metabolic state. Cell 158, 1293–1308 (2014).

    CAS  PubMed  Google Scholar 

  153. McDonough, A. A. & Thomson, S. C. in Brenner & Rector's The Kidney (eds Taal, M. W. et al.) (Elsevier Health Sciences, 2012).

  154. Wirthensohn, G. & Guder, W. G. Renal substrate metabolism. Physiol. Rev. 66, 469–497 (1986).

    CAS  PubMed  Google Scholar 

  155. Xu, Z. et al. Microtubules acquire resistance from mechanical breakage through intralumenal acetylation. Science 356, 328–332 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Watnick, T. & Germino, G. From cilia to cyst. Nat. Genet. 34, 355–356 (2003).

    CAS  PubMed  Google Scholar 

  157. Braun, D. A. & Hildebrandt, F. Ciliopathies. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a028191 (2017).

    Google Scholar 

  158. Ma, M., Gallagher, A. R. & Somlo, S. Ciliary mechanisms of cyst formation in polycystic kidney disease. Cold Spring Harb. Perspect. Biol. 9, a028209 (2017).

    PubMed  PubMed Central  Google Scholar 

  159. Yoder, B. K., Hou, X. & Guay-Woodford, L. M. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J. Am. Soc. Nephrol. 13, 2508–2516 (2002).

    CAS  PubMed  Google Scholar 

  160. Liu, X. et al. Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium. eLife 7, e33183 (2018).

    Google Scholar 

  161. Ma, M., Tian, X., Igarashi, P., Pazour, G. J. & Somlo, S. Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat. Genet. 45, 1004–1012 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Davenport, J. R. et al. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr. Biol. 17, 1586–1594 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Oh, E. C., Vasanth, S. & Katsanis, N. Metabolic regulation and energy homeostasis through the primary cilium. Cell Metab. 21, 21–31 (2015).

    CAS  PubMed  Google Scholar 

  164. Pampliega, O. et al. Functional interaction between autophagy and ciliogenesis. Nature 502, 194–200 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Tang, Z. et al. Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites. Nature 502, 254–257 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Cianfanelli, V. & Cecconi, F. Cell biology: molecular clearance at the cell's antenna. Nature 502, 180–181 (2013).

    CAS  PubMed  Google Scholar 

  167. Belibi, F. et al. Hypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD). Am. J. Physiol. Renal Physiol. 300, F1235–F1243 (2011).

    CAS  Google Scholar 

  168. Zhu, P., Sieben, C. J., Xu, X., Harris, P. C. & Lin, X. Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model. Hum. Mol. Genet. 26, 158–172 (2017).

    CAS  PubMed  Google Scholar 

  169. Boehlke, C. et al. Primary cilia regulate mTORC1 activity and cell size through Lkb1. Nat. Cell Biol. 12, 1115–1122 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Viau, A. et al. Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney. EMBO J. 37, e98615 (2018).

    PubMed  PubMed Central  Google Scholar 

  171. Praetorius, H. A. & Spring, K. R. Bending the MDCK cell primary cilium increases intracellular calcium. J. Membr. Biol. 184, 71–79 (2001).

    CAS  PubMed  Google Scholar 

  172. O'Toole, J. F. et al. Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. J. Clin. Invest. 120, 791–802 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Hoff, S. et al. ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3. Nat. Genet. 45, 951–956 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Majumder, S. & Fisk, H. A. VDAC3 and Mps1 negatively regulate ciliogenesis. Cell Cycle 12, 849–858 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Maldonado, E. N. & Lemasters, J. J. Warburg revisited: regulation of mitochondrial metabolism by voltage-dependent anion channels in cancer cells. J. Pharmacol. Exp. Ther. 342, 637–641 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Martel, C., Wang, Z. & Brenner, C. VDAC phosphorylation, a lipid sensor influencing the cell fate. Mitochondrion 19 (Pt A), 69–77 (2014).

    CAS  PubMed  Google Scholar 

  177. Huen, S. C. & Cantley, L. G. Macrophages in renal injury and repair. Annu. Rev. Physiol. 79, 449–469 (2017).

    CAS  PubMed  Google Scholar 

  178. Lee, S. et al. Distinct macrophage phenotypes contribute to kidney injury and repair. J. Am. Soc. Nephrol. 22, 317–326 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Karihaloo, A. et al. Macrophages promote cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 22, 1809–1814 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Swenson-Fields, K. I. et al. Macrophages promote polycystic kidney disease progression. Kidney Int. 83, 855–864 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Cassini, M. F. et al. Mcp1 promotes macrophage-dependent cyst expansion in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 29, 2471–2481 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Osborn, O. & Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363–374 (2012).

    CAS  PubMed  Google Scholar 

  183. Tan, Z. et al. Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J. Immunol. 194, 6082–6089 (2015).

    CAS  PubMed  Google Scholar 

  184. Sack, M. N. Mitochondrial fidelity and metabolic agility control immune cell fate and function. J. Clin. Invest. 128, 3651–3661 (2018).

    PubMed  PubMed Central  Google Scholar 

  185. West, A. P. & Shadel, G. S. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat. Rev. Immunol. 17, 363–375 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Gomes, L. C. & Scorrano, L. Mitochondrial elongation during autophagy: a stereotypical response to survive in difficult times. Autophagy 7, 1251–1253 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Monterisi, S. et al. PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling. eLife 6, e21374 (2017).

    PubMed  PubMed Central  Google Scholar 

  188. Chebib, F. T., Sussman, C. R., Wang, X., Harris, P. C. & Torres, V. E. Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat. Rev. Nephrol. 11, 451–464 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Meijer, E. et al. Copeptin, a surrogate marker of vasopressin, is associated with disease severity in autosomal dominant polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 6, 361–368 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Cerasola, G. et al. Sympathetic activity and blood pressure pattern in autosomal dominant polycystic kidney disease hypertensives. Am. J. Nephrol. 18, 391–398 (1998).

    CAS  PubMed  Google Scholar 

  191. Klein, I. H., Ligtenberg, G., Oey, P. L., Koomans, H. A. & Blankestijn, P. J. Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J. Am. Soc. Nephrol. 12, 2427–2433 (2001).

    CAS  PubMed  Google Scholar 

  192. Gomes, L. C., Di Benedetto, G. & Scorrano, L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat. Cell Biol. 13, 589–598 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Banales, J. M. et al. The cAMP effectors Epac and protein kinase A (PKA) are involved in the hepatic cystogenesis of an animal model of autosomal recessive polycystic kidney disease (ARPKD). Hepatology 49, 160–174 (2009).

    CAS  PubMed  Google Scholar 

  194. Masyuk, T. V. et al. Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases. Hepatology 58, 409–421 (2013).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

L.F.M. and G.G.G. are supported by the NIH intramural program of the NIDDK (1ZIADK075042).

Author information

Authors and Affiliations

  1. National Institutes of Health, Kidney Disease Branch/National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD, USA

    Luis Fernando Menezes & Gregory G. Germino

Authors
  1. Luis Fernando Menezes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregory G. Germino
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.F.M and G.G.G. wrote the text. G.G.G. reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to Luis Fernando Menezes or Gregory G. Germino.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Menezes, L.F., Germino, G.G. The pathobiology of polycystic kidney disease from a metabolic viewpoint. Nat Rev Nephrol 15, 735–749 (2019). https://doi.org/10.1038/s41581-019-0183-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-019-0183-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing