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Fructose might be a clue to the origin of preeclampsia insights from nature and evolution

Hypertension Research volume 46, pages 646–653 (2023)Cite this article

Abstract

Preeclampsia is a hypertensive disorder of pregnancy and is due to abnormal placentation. The pathogenesis remains unclear. Fructose is biologically distinct from glucose and has a critical role in fetal growth in early pregnancy. Many species, including humans, produce fructose in their placenta during the first trimester to assist fetal growth and survival during a time when hypoxia is significant. Fructose is preferred over glucose in hypoxic tissues, and in the developing fetus, fructose has a critical role in stimulating the production of nucleic acids, lipids and glycosaminoglycans. Fructose production normally decreases significantly following the establishment of maternal-fetal circulation following placentation. However, if there is impaired placentation, local hypoxia will continue to drive fructose production. Excessive fructose metabolism drives endothelial dysfunction, oxidative stress, elevated blood pressure, insulin resistance, fatty liver, and a rise in uric acid and vasopressin levels, all of which are features of the preeclamptic state. In addition to fructose production, dietary fructose, for example, from soft drinks, would be additive and has been reported to be a strong independent risk factor for preeclampsia. Uric acid-associated endothelial dysfunction disturbs the invasion of the spiral artery, leading to placental ischemia and further placental hypoxia. Here, we summarize the previous literature regarding the physiological and pathological roles of fructose in pregnancy and propose studies to further investigate the pathogenesis of preeclampsia.

Fructose might be a Clue to the Origin of Preeclampsia Insights from Nature and Evolution Preeclampsia is a hypertensive disorder of pregnancy. The pathogenesis remains unclear. Fructose has a critical role in fetal growth in early pregnancy, and might be a key role to developing preeclampsia. Here, we summarize the previous literatures regarding the physiological andpathological roles of fructose in pregnancy to propose studies to further investigate the pathogenesis of preeclampsia.

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Author notes

  1. These authors contributed equally: Miguel A. Lanaspa, Richard J. Johnson

Authors and Affiliations

  1. Department of Regenerative Medicine Development, Shiga University of Medical Science, Shiga, Japan

    Takahiko Nakagawa & Hideto Kojima

  2. Department of Biocommunication Development, Shiga University of Medical Science, Shiga, Japan

    Takahiko Nakagawa & Hideto Kojima

  3. Division of Renal Diseases and Hypertension, University of Colorado Denver, Colorado, CO, USA

    Ana Andres-Hernando, Miguel A. Lanaspa & Richard J. Johnson

  4. Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Tomoki Kosugi

  5. Department of Cardio-Renal Physiopathology, Instituto Nacional de Cardiología Ignacio Chavez, CP 14080, Mexico City, Mexico

    Laura G. Sanchez-Lozada

  6. Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

    Peter Stenvinkel & Karolina Kublickiene

  7. Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    S. Ananth Karumanchi

  8. Division of Nephrology, Department of Internal Medicine, Ewha Womans University College of Medicine, Ewha Medical Research Center, Seoul, Republic of Korea

    Duk-Hee Kang

  9. Department of Nephrology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Instituto Nacional de Cardiologia Ignacio Chavez, Mexico City, 14080, Mexico

    Bernardo Rodriguez-Iturbe

  10. Department of Biology, Boston University, Boston, MA, USA

    Dean R. Tolan

  11. Division of Kidney Disease, Rocky Mountain Veterans Administration Hospital, Aurora Colorado, CO, USA

    Richard J. Johnson

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  1. Takahiko Nakagawa
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Correspondence to Takahiko Nakagawa.

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Conflict of interest

MAL, DRT, LGL, and RJJ have shares in a start-up company developing fructokinase inhibitors (Colorado Research Partners LLC). TN and RJJ have shares in XORTX therapeutics, which is developing novel xanthine oxidase inhibitors. Dr. Johnson is a consultant for Horizon Pharmaceuticals, Inc. Dr. Karumanchi is a coinventor on patents for the use of angiogenic biomarkers in preeclampsia, has served as consultant for Roche and Thermo Fisher Scientific and has financial interest in Aggamin Pharmaceuticals and Comanche Biopharma. All other authors declare no conflicts of interest.

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Nakagawa, T., Ana Andres-Hernando, Kosugi, T. et al. Fructose might be a clue to the origin of preeclampsia insights from nature and evolution. Hypertens Res 46, 646–653 (2023). https://doi.org/10.1038/s41440-022-01121-w

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