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Autophagy-Based Diagnosis of Pregnancy Hypertension and Pre-Eclampsia

  • Surendra Sharma
    Correspondence
    Address correspondence to Surendra Sharma, M.D., Ph.D., Department of Pediatrics, Women and Infants Hospital, 101 Dudley St., Providence, RI 02905.
    Affiliations
    Department of Pediatrics, Women and Infants Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
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Open ArchivePublished:September 19, 2018DOI:https://doi.org/10.1016/j.ajpath.2018.09.001
      In this issue of The American Journal of Pathology, Aoki et al
      • Aoki A.
      • Nakshima A.
      • Kusabiraki T.
      • Ono Y.
      • Yoshino O.
      • Muto M.
      • Kumasawa K.
      • Yoshimori T.
      • Ikawa M.
      • Saito S.
      Trophoblast-specific conditional ATG7 knockout mice develop gestational hypertension.
      present evidence that placental Atg7 deficiency in conditional Atg7 knockout mice may cause pregnancy-associated hypertension, a primary diagnostic feature of pre-eclampsia. Pre-eclampsia is a major complication of pregnancy that is diagnosed by de novo onset of hypertension often with proteinuria after 20 weeks of gestation and affects 5% to 8% pregnancies with higher incidence in low resource settings.
      • Sibai B.
      • Dekker G.
      • Kupferminc M.
      Pre-eclampsia.
      • Wildman K.
      • Bouvier-Colle M.H.
      Maternal mortality as an indicator of obstetric care in Europe.
      • Cheng S.-B.
      • Sharma S.
      Preeclampsia and health risks later in life: an immunological link.
      • Vikse B.E.
      • Irgens L.M.
      • Leivestad T.
      • Skjaerven R.
      • Iversen B.M.
      Preeclampsia and the risk of end-stage renal disease.
      • Smith G.C.
      • Pell J.P.
      • Walsh D.
      Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births.
      • Roberts J.M.
      • Hubel C.A.
      Is oxidative stress the link in the two stage model of preeclampsia?.
      • Redman C.W.
      • Sacks G.P.
      • Sargent I.L.
      Preeclampsia: an excessive maternal inflammatory response to pregnancy.
      • Burton G.J.
      • Yung H.W.
      Endoplasmic reticulum stress in the pathogenesis of early-onset pre-eclampsia.
      It is a leading cause of maternal and fetal morbidity and mortality and represents a pivotal risk factor for chronic diseases, including cardiovascular disease, diabetes mellitus, and renal disease.
      • Sibai B.
      • Dekker G.
      • Kupferminc M.
      Pre-eclampsia.
      • Wildman K.
      • Bouvier-Colle M.H.
      Maternal mortality as an indicator of obstetric care in Europe.
      • Cheng S.-B.
      • Sharma S.
      Preeclampsia and health risks later in life: an immunological link.
      • Vikse B.E.
      • Irgens L.M.
      • Leivestad T.
      • Skjaerven R.
      • Iversen B.M.
      Preeclampsia and the risk of end-stage renal disease.
      • Smith G.C.
      • Pell J.P.
      • Walsh D.
      Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births.
      • Roberts J.M.
      • Hubel C.A.
      Is oxidative stress the link in the two stage model of preeclampsia?.
      • Redman C.W.
      • Sacks G.P.
      • Sargent I.L.
      Preeclampsia: an excessive maternal inflammatory response to pregnancy.
      • Burton G.J.
      • Yung H.W.
      Endoplasmic reticulum stress in the pathogenesis of early-onset pre-eclampsia.
      This devastating pregnancy disorder is associated with multi-organ injury and on the fetal side, is invariably complicated with fetal growth restriction. Although the etiology of pre-eclampsia, particularly pregnancy hypertension and end organ injury, is still poorly understood, it is widely accepted that poor placentation coupled with local and systemic inflammation is the major causative factor. At the maternal-fetal interface, several detrimental events including defective spiral artery remodeling, hypoxia/ischemia microenvironment, reperfusion injury, and excessive production of pregnancy-incompatible factors such as anti-angiogenic factors, inflammatory cytokines, and alarmins are well documented.
      • Roberts J.M.
      • Hubel C.A.
      Is oxidative stress the link in the two stage model of preeclampsia?.
      • Redman C.W.
      • Sacks G.P.
      • Sargent I.L.
      Preeclampsia: an excessive maternal inflammatory response to pregnancy.
      • Burton G.J.
      • Yung H.W.
      Endoplasmic reticulum stress in the pathogenesis of early-onset pre-eclampsia.
      • Levine R.J.
      • Maynard S.E.
      • Qian C.
      • Lim K.H.
      • England L.J.
      • Yu K.F.
      • Schisterman E.F.
      • Thadhani R.
      • Sachs B.P.
      • Epstein F.H.
      • Sibai B.M.
      • Sukhatme V.P.
      • Karumanchi S.A.
      Circulating angiogenic factors and the risk of preeclampsia.
      The circulating factors are thought to program the onset of hypertension and other pre-eclampsia-like features. What may lead to poor placentation? Recently, presence of toxic protein aggregates in the placenta as well as in serum and urine has been demonstrated.
      • Kalkunte S.S.
      • Neubeck S.
      • Norris W.E.
      • Cheng S.B.
      • Kostadinov S.
      • Vu Hoang D.
      • Ahmed A.
      • von Eggeling F.
      • Shaikh Z.
      • Padbury J.
      • Berg G.
      • Olofsson A.
      • Markert U.R.
      • Sharma S.
      Transthyretin is dysregulated in preeclampsia, and its native form prevents the onset of disease in a preclinical mouse model.
      • Buhimschi I.A.
      • Nayeri U.A.
      • Zhao G.
      • Shook L.L.
      • Pensalfini A.
      • Funai E.F.
      • Bernstein I.M.
      • Glabe C.G.
      • Buhimschi C.S.
      Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia.
      • McCarthy F.P.
      • Adetoba A.
      • Gill C.
      • Bramham K.
      • Bertolaccini M.
      • Burton G.J.
      • Girardi G.
      • Seed P.T.
      • Poston L.
      • Chappell L.C.
      Urinary congophilia in women with hypertensive disorders of pregnancy and preexisting proteinuria or hypertensin.
      These protein aggregates can also be part of the placental exosome cargo and can be induced in human trophoblasts by hypoxia or inflammatory cytokines.
      • Tong M.
      • Cheng S.B.
      • Chen Q.
      • DeSousa J.
      • Stone P.R.
      • James J.L.
      • Chamley L.W.
      • Sharma S.
      Aggregated transthyretin is specifically packaged into placental nano-vesicles in preeclampsia.
      Importantly, they cause trophoblast cell death and induce pre-eclampsia-like pathology in pregnant mice.
      • Kalkunte S.S.
      • Neubeck S.
      • Norris W.E.
      • Cheng S.B.
      • Kostadinov S.
      • Vu Hoang D.
      • Ahmed A.
      • von Eggeling F.
      • Shaikh Z.
      • Padbury J.
      • Berg G.
      • Olofsson A.
      • Markert U.R.
      • Sharma S.
      Transthyretin is dysregulated in preeclampsia, and its native form prevents the onset of disease in a preclinical mouse model.
      Why these protein aggregates not cleared from the placenta? Autophagy is a mechanism inside a cell that degrades damaged organelles and proteins for reuse.
      • Mizushima N.
      • Levine B.
      • Cuervo A.M.
      • Klionsky D.J.
      Autophagy fights disease through cellular self-digestion.
      • Nakatogawa H.
      • Suzuki K.
      • Kamada Y.
      • Ohsumi Y.
      Dynamics and diversity in autophagy mechanisms: lessions from yeast.
      However, overwhelming environmental factors and/or intracellular stress may impair autophagy by inducing excessive toxic protein aggregation or damage beyond repair. In this regard, numerous studies have established a relationship between autophagy and various human diseases, particularly neurodegenerative diseases.
      • Mizushima N.
      • Levine B.
      • Cuervo A.M.
      • Klionsky D.J.
      Autophagy fights disease through cellular self-digestion.
      • Nakatogawa H.
      • Suzuki K.
      • Kamada Y.
      • Ohsumi Y.
      Dynamics and diversity in autophagy mechanisms: lessions from yeast.
      It is unclear if the presence of protein aggregates in hypertensive pre-eclampsia syndrome a result of impaired autophagy.

      Autophagy and ATG7

      Prof. Yoshinori Ohsumi, who received the 2016 Noble Prize in Physiology or Medicine on his work on autophagy, recently provided a chronological description of historical research landmarks on autophagy.
      • Ohsumi Y.
      Historical landmarks of autophagy research.
      According to him, the year of 2013 marked the 50th anniversary of Christian de Duve's coining of the term “autophagy” for the degradation process of cytoplasmic constituents. In other words, autophagy is a lysosome-mediated intracellular bulk or selective degradation system to remove toxic macromolecules and organelles, thus maintaining cellular homeostasis and metabolism. Autophagy has been described to be a regulatory mechanism in all cellular organisms, including yeast, and regulates cellular growth and differentiation, remodeling and health, adaptation to stress, control or propagation of viral infections, and tumor suppression. The number of research articles on autophagy has ballooned up exponentially by the year 2013 and continues to grow.
      • Ohsumi Y.
      Historical landmarks of autophagy research.
      The autophagy-related genes (ATG) have been characterized and now the number of these genes has increased to 37, involved in the core machinery of the autophagosome assembly and in the selective modes of autophagy.
      • Nakatogawa H.
      • Suzuki K.
      • Kamada Y.
      • Ohsumi Y.
      Dynamics and diversity in autophagy mechanisms: lessions from yeast.
      The ATG proteins involved in the autophagosome assembly are made up of several functional units. Several functional combinations of ATG proteins are involved in regulating autophagy.
      • Yamaguchi J.
      • Suzuki C.
      • Nano T.
      • Kakuta S.
      • Ozawa K.
      • Tanida I.
      • Saitoh T.
      • Sunabori T.
      • Komatsu M.
      • Tanaka K.
      • Aoki S.
      • Sakimura K.
      • Uchiyama Y.
      Atg9a deficiency causes axon-specific lesions including neuronal circuit dysgenesis.
      These systems mostly work in concert as ATG7, ATG3, and ATG5 complexed with ATG12 and ATG16 are required for the ATG8-phosphatydylethanolamine conjugation system (Figure 1). This complex and highly choreographed regulatory machinery of autophagy is required to maintain cellular health. The mechanisms of action of ATG proteins have been partially studied using knockout mouse models involving individual ATG genes. For example, ATG7 deficiency results in fetal death just after delivery and its liver-specific deficient mice exhibit p62 accumulation in the cytoplasm of hepatocytes.
      • Komatsu M.
      • Waguri S.
      • Koike M.
      • Sou Y.S.
      • Ueno T.
      • Hara T.
      • Mizushima N.
      • Iwata J.
      • Ezaki J.
      • Murata S.
      • Hamazaki J.
      • Nishito Y.
      • Iemura S.
      • Natsume T.
      • Yanagawa T.
      • Uwayama J.
      • Warabi E.
      • Yoshida H.
      • Ishii T.
      • Kobayashi A.
      • Yamamoto M.
      • Yue Z.
      • Uchiyama Y.
      • Kominami E.
      • Tanaka K.
      Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
      The p62 protein serves as a substrate of autophagy and presents ubiquitin-conjugated proteins to the phagophore. Deletion of ATG7 in the central nervous system results in neuron death and abnormal limb reflexes.
      • Komatsu M.
      • Wang Q.J.
      • Holstein G.R.
      • Friedrich V.L.
      • Iwata J.
      • Kominami E.
      • Chait B.T.
      • Tanaka K.
      • Yue Z.
      Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration.
      Thus, deficiency of the ATG genes may affect different organs and lead to fatal consequences due to energy depletion, accumulation of protein aggregates, and metabolic stress. Our knowledge of the role of autophagy and its related genes is still limited. Since ATG gene deficiency could be lethal, one way to study its specific effects is to generate conditional knockout strains. In the article by Aoki et al,
      • Aoki A.
      • Nakshima A.
      • Kusabiraki T.
      • Ono Y.
      • Yoshino O.
      • Muto M.
      • Kumasawa K.
      • Yoshimori T.
      • Ikawa M.
      • Saito S.
      Trophoblast-specific conditional ATG7 knockout mice develop gestational hypertension.
      the authors have used such an approach to study the role of ATG7 in the placenta and to correlate it with pregnancy complications such as hypertension and pre-eclampsia.
      Figure thumbnail gr1
      Figure 1Schematic diagram showing the role of ATG7-like protein in the autophagy machinery and the effect of its deficiency on placentation and programming of pregnancy complications such as preeclampsia.

      Autophagy, Placenta, and Pregnancy

      It has been proposed that autophagy acts as a guard to the placenta against pathogens and stress.
      • Delorme-Axford E.
      • Donker R.B.
      • Mouillet J.F.
      • Chu T.
      • Bayer A.
      • Ouyang Y.
      • Wang T.
      • Stolz D.B.
      • Sarkar S.N.
      • Morelli A.E.
      • Sadovsky Y.
      • Coyne C.B.
      Human placental trophoblasts confer viral resistance to recipient cells.
      • Hung T.H.
      • Hsieh T.T.
      • Chen S.F.
      • Li M.J.
      • Yeh Y.L.
      Autophagy in the human placenta throughout gestation.
      Curiously, placental autophagy can also be exploited by pathogens to evade surveillance from host defenses.
      • Cao B.
      • Parnell L.A.
      • Diamond M.S.
      • Mysorekar I.U.
      Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice.
      Several reports have also suggested that autophagy is hyper-activated in the placenta of women diagnosed with pre-eclampsia.
      • Gao L.
      • Qui H.B.
      • Kamana K.C.
      • Zhang X.M.
      • Zhang H.
      • Baker P.N.
      Excessive autophagy induces the failure of trophoblast invasion and vasculature: possible relevance to the pathogenesis of preeclampsia.
      • Melland-Smith M.
      • Ermini L.
      • Chauvin S.
      • Craig-Barnes H.
      • Tagliaferro A.
      • Todros T.
      • Post M.
      • Caniggia I.
      Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia.
      However, excessive autophagy may not explain why there is placental accumulation of protein aggregates in pre-eclampsia. It was unclear if placenta-specific conditional Atg7 deficiency causes pre–eclampsia-like features in pregnant dams, including elevated blood pressure (hypertension), proteinuria, fetal growth restriction, placental hypoxic injury, and glomerular endotheliosis. Aoki et al
      • Aoki A.
      • Nakshima A.
      • Kusabiraki T.
      • Ono Y.
      • Yoshino O.
      • Muto M.
      • Kumasawa K.
      • Yoshimori T.
      • Ikawa M.
      • Saito S.
      Trophoblast-specific conditional ATG7 knockout mice develop gestational hypertension.
      present data that suggest that in conditional mice (Atg7cKO), there was placental-, not fetal-, specific accumulation of p62. Atg7cKO mice showed elevated blood pressure during pregnancy, reduced levels of placental growth factor, and small placenta. Importantly, Atg7cKO mice showed poor trophoblast invasion and apoptosis as compared to control EGFP mice, critical features observed in the placenta of pre-eclampsia deliveries. Although Atg7cKO mice do not experience the severe pathological features of pre-eclampsia, it is possible that other factors in addition to ATG7 contribute to the onset of severe pre-eclampsia pathology. For example, Il10 KO mice exhibit full spectrum pre-eclampsia-like features compared to their wild-type counterparts, suggesting that IL-10 provides partial protective effects.
      • Kalkunte S.
      • Boij R.
      • Norris W.
      • Friedman J.
      • Lai Z.
      • Kurtis J.
      • Lim K.H.
      • Padbury J.F.
      • Matthiesen L.
      • Sharma S.
      Sera from preeclampsia patients elicit symptoms of human disease in mice and provide a basis for an in vitro predictive assay.
      It will be interesting to see the status of protein aggregates in the placenta of Atg7cKO mice for better understanding of the placental pathology. Another important question that arises in the context of partial pathology of pre-eclampsia-like features in Atg7cKO mice is whether the Atg7 deficiency is total or partial. In the article by Aoki et al,
      • Aoki A.
      • Nakshima A.
      • Kusabiraki T.
      • Ono Y.
      • Yoshino O.
      • Muto M.
      • Kumasawa K.
      • Yoshimori T.
      • Ikawa M.
      • Saito S.
      Trophoblast-specific conditional ATG7 knockout mice develop gestational hypertension.
      trophoblast-specific conditional Atg7−/− mice are shown to exhibit significant elevation in blood pressure (hypertension), reduced expression of placental growth factor, and smaller placenta with no changes in proteinuria and fetal growth restriction. This raises an important question whether combination of deficiency in another ATG gene as well as Atg7 will result in the full spectrum of severe pathology of pre-eclampsia.

      Autophagy-Based Diagnosis and Treatment

      The chronic exposure to detrimental triggers may induce protein aggregation and cause impaired autophagy, resulting in placental toxicity and trophoblast cell death and eventually placental insufficiency (Figure 1). Thus early detection of protein aggregates in serum using autophagy-deficient trophoblast cells can be used as a diagnostic tool. Poor placentation due to autophagy deficiency may further lead to production of anti-angiogenic factors, inflammatory cytokines, cell-free DNA, and extracellular vesicles to program systemic manifestation of hypertension and endothelium dysregulation. Taken together, a therapeutic strategy can be proposed based on inhibition of protein aggregation and autophagy restoration.

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      Linked Article

      • Trophoblast-Specific Conditional Atg7 Knockout Mice Develop Gestational Hypertension
        The American Journal of PathologyVol. 188Issue 11
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          Hypertensive disorder of pregnancy (HDP) is a serious pregnancy complication that is life threatening to both the mother and fetus. Understanding HDP pathophysiology is important for developing medical treatments. This study demonstrates the involvement of autophagy deficiency in adverse maternal and fetal outcomes using trophoblast-specific autophagy related (Atg)7, an autophagy-related protein, knockout mice. Atg7 conditional knockout (cKO) placentas were significantly smaller than controls in the spongiotrophoblast layer but not the labyrinth layer, which significantly elevated blood pressure in dams.
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