Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 2198 word(s) 2198 2021-07-15 08:47:28 |
2 update references and layout Meta information modification 2198 2021-11-10 04:34:36 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Sun, Y. Megalin. Encyclopedia. Available online: (accessed on 22 June 2024).
Sun Y. Megalin. Encyclopedia. Available at: Accessed June 22, 2024.
Sun, Yuan. "Megalin" Encyclopedia, (accessed June 22, 2024).
Sun, Y. (2021, November 09). Megalin. In Encyclopedia.
Sun, Yuan. "Megalin." Encyclopedia. Web. 09 November, 2021.

Megalin, a recently discovered endocytic receptor for prorenin and renin, not only contributes to renin/prorenin reabsorption in the proximal tubule of the kidney, but simultaneously plays a role in renal Ang II generation, although how exactly this occurs is still unknown . 

pre-eclampsia renin–angiotensin system megalin proton pump inhibitors

1. Introduction

Pre-eclampsia is a hypertensive disorder characterized by new-onset hypertension and proteinuria occurring after 20 weeks of gestation. It is one of the major causes of worldwide maternal mortality and morbidity [1][2][3]. A normal pregnancy requires a ≈30% increase in extracellular fluid volume to provide an adequate blood supply for the developing uterus, placenta and fetus [4]. The renin–angiotensin system (RAS) plays a key role in this process. Estrogen stimulates hepatic angiotensinogen (AGT) expression, resulting in a 3–5-fold rise in circulating AGT [4][5]. The plasma renin concentration also rises modestly [6], and together with the rise in AGT, this results in a significant rise in plasma renin activity (PRA); thus, ensuring sufficient RAS activity to allow water and salt retention [7][8]. Remarkably, plasma prorenin levels increase much more strongly than plasma renin levels [6][9], due to prorenin release from the ovaries and, to a lesser degree, the placenta [10]. The function of this prorenin remains unclear.
In pre-eclampsia, the rise in renin and AGT in the circulation is suppressed, although sensitivity to angiotensin (Ang) II is enhanced [11]. Circulating prorenin levels in pre-eclamptic women are in the normal pregnancy range [12]. Given the local production of prorenin in the placenta, while the placenta is a key player in the development of pre-eclampsia, disturbed placental RAS activity may contribute to this phenomenon. Yet, data on prorenin levels in the uteroplacental unit of pre-eclamptic women are conflicting, with evidence for decreases, increases and no alteration [13][14][15]. What exactly determines the distribution of prorenin across the ovaries and uteroplacental unit, as well as its release into the blood stream, is unknown. It may require transcellular transport. For instance, amniotic fluid prorenin is of chorionic origin [16], implying that chorionic prorenin is capable of crossing the amnion membrane. A novel player in this field is megalin. Megalin, a recently discovered endocytic receptor for prorenin and renin, not only contributes to renin/prorenin reabsorption in the proximal tubule of the kidney, but simultaneously plays a role in renal Ang II generation, although how exactly this occurs is still unknown [17]. Outside the kidney, megalin is present in syncytiotrophoblast and cytotrophoblast cells in the placenta [18]. Membrane recycling of megalin is a fast process which relies on vacuolar H+-ATPase (V-ATPase)-dependent endosomal acidification [19]. The latter involves the so-called (pro)renin receptor ((P)RR), which is an accessory protein of V-ATPase. Here, it is of interest to note that proton pump inhibitors (PPIs) have been observed to lower the placental release of soluble Fms-like tyrosine kinase-1 (sFlt-1), a mediator of maternal endothelial dysfunction in pre-eclampsia [20][21]. Ang II is a stimulator of sFlt-1 [22]. Although PPIs are capable of inhibiting V-ATPase [23][24], such inhibition did not contribute to their acute effects on sFlt-1 release from human trophoblast cells [25]. A further possibility is that PPIs affect sFlt-1 production indirectly, by preventing RAS component transport/uptake.

2. Expression of RAS Components in Healthy and Pre-Eclamptic Placentas

Placental expression of renin, AGT, angiotensin-converting enzyme (ACE), ACE2, the Ang II type 1 and type 2 receptor (AT1R, AT2R), and megalin was comparable between healthy and pre-eclamptic placentas (n = 12 for each), while (P)RR expression was increased in the latter (Figure 1A–H). AGT expression was at or below the detection limit (Ct = 38) in most of the samples, even when using two additional sets of primers (Figure 1I,J). Total renin levels in healthy placental tissue amounted to 118 (range 42.5–1476) pg/g tissue, and 72 ± 2% of this was prorenin (Figure 2A–C; n = 16). Total renin levels were significantly (p < 0.05) higher in pre-eclamptic placentas (266 (range 54.5–1568) pg/g tissue), and this was due to upregulated prorenin (p < 0.05) rather than renin. Nevertheless, the proportion of renin in the pre-eclamptic group (29 ± 2%) was not different from that in healthy placentas. Placental AGT abundance was decreased (p < 0.0001) in pre-eclamptic placentas (Figure 2D,E), while the opposite was true (p < 0.01) for megalin protein abundance (Figure 2F,G).

Figure 1. Gene expression levels of RAS components (AG) and megalin (H) in healthy and early-onset pre-eclamptic (EoPE) placental tissue. (I,J): AGT expression was confirmed with different pairs of primers. Data are mean ± SEM of n = 12. * p < 0.05. (P)RR, (pro)renin receptor; AGT, angiotensinogen; ACE, angiotensin-converting enzyme; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; A.U., arbitrary unit.
Figure 2. Total renin (A), renin (B) and prorenin (C) levels (n = 16) measured by immunoradiometric assay and angiotensinogen (AGT; D,E) and megalin (F,G) protein abundance (n = 12) measured by Western blot in healthy and early-onset pre-eclamptic (EoPE) placental tissue. Panels (D,F) are representative blots of AGT and megalin protein. Data were normalized versus GAPDH (E) or β-actin (G). Data are mean ± SEM. * p < 0.05, ** p < 0.005, *** p < 0.0005 vs. Healthy. AGT, angiotensinogen.

3. Placental Release of (Pro)renin and AGT

Prorenin release into the maternal perfusate from both healthy (n = 5) and pre-eclamptic (n = 6) placentas remained stable over the entire perfusion period. In two pre-eclamptic placenta perfusions, the perfusion had to be stopped after 90 min because of leakage. Release of prorenin tended to be higher from pre-eclamptic placentas, although significance was reached at two time points only (Figure 3A). Renin release paralleled prorenin release, albeit at >10-fold lower levels (Figure 3B). In contrast, placental AGT release from both healthy and pre-eclamptic placentas peaked initially, and then displayed a steady decline, so that the release was lowest after 180 min (Figure 3C). Neither for renin, nor for AGT, were there differences observed between healthy and pre-eclamptic placentas.
Figure 3. Prorenin (A), renin (B) and angiotensinogen (C) release from isolated perfused healthy (n = 5) and early-onset pre-eclamptic (EoPE, n = 6) cotyledons. AGT: angiotensinogen. Perfusate collection from two of the pre-eclamptic placentas could not be continued over the full 180 min due to fetal-to-maternal leakage. In such cases, only the samples prior to the occurrence of leakage were used. Data are mean ± SEM. * p < 0.05.

4. Megalin Internalizes AGT and PPI Decreases Renin Internalization but Not Binding in BN16 Cells

Megalin is known to be a receptor for both renin and prorenin [26]. To verify whether it also binds and internalizes AGT, we incubated BN16 cells with tagged AGT. BN16 cells accumulated AGT following a 2 h incubation period (Figure 4A). Inhibiting megalin expression greatly suppressed this accumulation, confirming that megalin also underlies AGT uptake (Figure 4B,C). We next tested whether the PPI esomeprazole regulates renin binding and internalization. Esomeprazole dose-dependently reduced renin uptake in BN16 cells, but did not affect renin binding (Figure 4D,E). This fully paralleled the effect of bafilomycin A1 (Figure 4F,G), and illustrates that esomeprazole, such as bafilomycin A1, interferes with the megalin-mediated internalization process.
Figure 4. Panels (AC): representative blots of His-AGT protein abundance in BN16 cells treated with negative control (siNC) or siRNA against megalin (siMegalin). Panels, (DG): cell-associated renin levels after incubating BN16 cells with 100 U/L renin at 37 °C (D,F) or 4 °C (E,G) for 2 h in the presence of increasing concentrations of esomeprazole (D,E) or bafilomycin A1 (F,G). Data are mean ± SEM of n = 5–9. ** p < 0.005, *** p < 0.0005 vs. control.

5. PPI Reduces sFlt-1 Secretion in Human Placental Villous Explants

As expected, pre-eclamptic placenta explants release more sFlt-1 than healthy placenta explants (Figure 5A). This is in agreement with the increased Flt-1 expression in pre-eclamptic explants (Figure 5B). Esomeprazole-suppressed Flt-1 expression and sFlt-1 release particularly in pre-eclamptic explants and, as a consequence, Flt-1 expression in pre-eclamptic explants after this drug was identical to that in healthy placenta explants.
Figure 5. sFlt-1 levels in medium (A) and mRNA levels in explants (B) after incubating healthy or pre-eclamptic (EoPE) placental villous explants with 100 μM of esomeprazole (Eso) for 48 h. sFlt-1 level: healthy n = 18, EoPE n = 8; Flt-1 mRNA level: healthy n = 7, EoPE n = 4. * p < 0.05, ** p < 0.005, *** p < 0.0005 vs. 0. A.U., arbitrary unit.

6. Discussion

The existence of a placental RAS has been proposed decades ago [27]. Although it is believed that it may contribute to pre-eclampsia, its exact role is still unknown. This relates to the fact that we still do not fully understand how local Ang II synthesis occurs in the placenta. In the current study, we found that the mRNA levels of RAS components are comparable in healthy and pre-eclamptic placentas. This agrees with previous studies showing that renin, AGT, ACE and AT2R expression are similar in normal and pre-eclamptic decidua basalis [15][28][29]. Simultaneously, uteroplacental AT1R [29][30][31] and renin [31] upregulation have also been claimed to be involved in the pathogenesis of pre-eclampsia. One explanation for these conflicting observations is that different tissues were studied, ranging from endometrium and myometrium to decidual tissue. In our study, we collected tissue from the maternal side of the placenta, i.e., decidua basalis and part of chorionic villi. A second explanation is that placental RAS expression may change with increasing gestational age [31]
Importantly, placental AGT expression in the present study was low and in most cases undetectable. Such low expression was observed earlier, when making a comparison with prolactin and renin using Northern blot analysis [32]. In situ mRNA detection via the padlock probes method also did not detect AGT expression in the placenta [33]. Despite the absence of significant expression, AGT protein was easily detectable in placental tissue. This implies that placental AGT must have been taken up from maternal blood. In agreement with this concept, placental AGT levels were lower in pre-eclamptic women, who are known to have greatly diminished circulating AGT levels. Moreover, perfusing the placenta with buffer resulted in a washout of AGT. Animal data similarly support a major role for AGT of maternal origin. When female mice carrying the human renin transgene were crossed with male mice carrying the human AGT transgene (both of which do not react with their mouse counterparts), the pregnant mice remained normotensive. Yet, when crossing female human AGT transgenic mice with male human renin transgenic mice, the pregnant mice did develop a pre-eclamptic phenotype, characterized by hypertension, elevated sFlt-1 levels and proteinuria [34]. Moreover, specifically inhibiting human AGT expression in the maternal liver with liver-targeted siRNA in the latter model suppressed the pre-eclamptic phenotype [35]. Taken together, these data imply that placental angiotensin generation relies on maternal AGT.
Unlike AGT release, which peaked immediately and then decreased, placental (pro)renin release remained stable over a 3 h perfusion period in healthy placentas. Since the total renin release in healthy placentas amounted to ≈2000 pg/h, and considering that a cotyledon wet weight amounted to ≈25 g, the total renin amount released during the 3 h perfusion period can be estimated to be 2500/25 × 3 = 300 pg/g. This is 2–3 times the amount detected in placental tissue. These data, therefore, strongly support the continuous synthesis and release of (pro)renin from the placenta, in full agreement with previous findings [27][36][37]. Importantly, the circulating renin levels in pre-eclamptic women are lower than those in healthy pregnant women, while their circulating prorenin levels mimic those in healthy pregnancy [12]. The present study observed 2-fold higher prorenin levels in pre-eclamptic placentas, while placental renin was identical in healthy and pre-eclamptic women. Placental (pro)renin release paralleled these latter observations. Taken together, these data suggest that placental (pro)renin synthesis occurs independently of renal (pro)renin synthesis. Yet, whether this results in independent upregulation of Ang II generation at placental tissue sites cannot be concluded, particularly since this would rely on the uptake of circulating AGT, which is lower in pre-eclampsia. Here, there might be a role for the megalin/V-ATPase pathway.
The (P)RR is an accessory protein of the V-ATPase. Its upregulation in pre-eclampsia, combined with increased megalin levels, favors increased activity of the megalin–V-ATPase pathway in this condition [17][38]. We recently reported that megalin is a novel endocytic receptor for (pro)renin in the kidney [26]. Inhibition of megalin and the (P)RR similarly suppressed endocytosis, without showing additive effects [25]. This confirms that megalin-mediated uptake relies on (P)RR/V-ATPase-dependent endosomal acidification. These data were obtained in BN16 cells, which predominantly express megalin, and no other renin/prorenin-binding receptors such as the mannose-6-phosphate receptor [26]. The latter receptor also occurs in trophoblast cells [39]. Using megalin-expressing BN16 cells, we were now able to show that the megalin–V-ATPase pathway also underlies AGT uptake. Moreover, we observed that the PPI esomeprazole, such as the V-ATPase inhibitor bafilomycin A1, inhibits megalin-mediated internalization. Given that megalin-mediated AGT uptake underlies renal angiotensin generation [17], we speculate that a similar phenomenon may occur in the placenta. Here, we emphasize that the greater sensitivity of pre-eclamptic women to Ang II [11][40] may imply that placental Ang II levels do not necessarily have to be higher than those in healthy placentas in order to exert the same or even a stronger effect. Onda et al. showed that PPIs lower sFlt-1 synthesis in placental explants (confirmed in the present study), but were unable to link this to a direct consequence of V-ATPase inhibition with bafilomycin A1 [25]. Our data now reveal a new option: PPIs might suppress placental RAS activity by interfering either with AGT uptake, with (pro)renin transport, or both. Since lower placental Ang II levels are expected to result in diminished sFlt-1 production, this concept offers a novel explanation for the observation that PPIs lower circulating sFlt-1 in pre-eclamptic women (Figure 6).
Figure 6. Schematic overview. AGT, angiotensinogen; 


  1. Mol, B.W.J.; Roberts, C.T.; Thangaratinam, S.; Magee, L.A.; de Groot, C.J.M.; Hofmeyr, G.J. Pre-eclampsia. Lancet 2016, 387, 999–1011.
  2. Miklus, R.M.; Elliott, C.; Snow, N. Surgical cricothyrotomy in the field: Experience of a helicopter transport team. J. Trauma 1989, 29, 506–508.
  3. Phipps, E.A.; Thadhani, R.; Benzing, T.; Karumanchi, S.A. Pre-eclampsia: Pathogenesis, novel diagnostics and therapies. Nat. Rev. Nephrol. 2019, 15, 275–289.
  4. Verdonk, K.; Visser, W.; Van Den Meiracker, A.H.; Danser, A.H. The renin-angiotensin-aldosterone system in pre-eclampsia: The delicate balance between good and bad. Clin. Sci. 2014, 126, 537–544.
  5. Rana, S.; Powe, C.E.; Salahuddin, S.; Verlohren, S.; Perschel, F.H.; Levine, R.J.; Lim, K.H.; Wenger, J.B.; Thadhani, R.; Karumanchi, S.A. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012, 125, 911–919.
  6. Derkx, F.H.; Alberda, A.T.; de Jong, F.H.; Zeilmaker, F.H.; Makovitz, J.W.; Schalekamp, M.A. Source of plasma prorenin in early and late pregnancy: Observations in a patient with primary ovarian failure. J. Clin. Endocrinol. Metab. 1987, 65, 349–354.
  7. Hsueh, W.A.; Luetscher, J.A.; Carlson, E.J.; Grislis, G.; Fraze, E.; McHargue, A. Changes in active and inactive renin throughout pregnancy. J. Clin. Endocrinol. Metab. 1982, 54, 1010–1016.
  8. Irani, R.A.; Xia, Y. Renin angiotensin signaling in normal pregnancy and preeclampsia. Semin. Nephrol. 2011, 31, 47–58.
  9. Sealey, J.E.; McCord, D.; Taufield, P.A.; Ales, K.A.; Druzin, M.L.; Atlas, S.A.; Laragh, J.H. Plasma prorenin in first-trimester pregnancy: Relationship to changes in human chorionic gonadotropin. Am. J. Obstet. Gynecol. 1985, 153, 514–519.
  10. Krop, M.; Danser, A.H. Circulating versus tissue renin-angiotensin system: On the origin of (pro)renin. Curr. Hypertens. Rep. 2008, 10, 112–118.
  11. Irani, R.A.; Xia, Y. The functional role of the renin-angiotensin system in pregnancy and preeclampsia. Placenta 2008, 29, 763–771.
  12. Verdonk, K.; Saleh, L.; Lankhorst, S.; Smilde, J.E.; van Ingen, M.M.; Garrelds, I.M.; Friesema, E.C.; Russcher, H.; van den Meiracker, A.H.; Visser, W.; et al. Association studies suggest a key role for endothelin-1 in the pathogenesis of preeclampsia and the accompanying renin-angiotensin-aldosterone system suppression. Hypertension 2015, 65, 1316–1323.
  13. Brar, H.S.; Kjos, S.L.; Dougherty, W.; Do, Y.S.; Tam, H.B.; Hsueh, W.A. Increased fetoplacental active renin production in pregnancy-induced hypertension. Am. J. Obstet. Gynecol. 1987, 157, 363–367.
  14. Kalenga, M.K.; Thomas, K.; de Gasparo, M.; De Hertogh, R. Determination of renin, angiotensin converting enzyme and angiotensin II levels in human placenta, chorion and amnion from women with pregnancy induced hypertension. Clin. Endocrinol. 1996, 44, 429–433.
  15. Herse, F.; Dechend, R.; Harsem, N.K.; Wallukat, G.; Janke, J.; Qadri, F.; Hering, L.; Muller, D.N.; Luft, F.C.; Staff, A.C. Dysregulation of the circulating and tissue-based renin-angiotensin system in preeclampsia. Hypertension 2007, 49, 604–611.
  16. Pringle, K.G.; Wang, Y.; Lumbers, E.R. The synthesis, secretion and uptake of prorenin in human amnion. Physiol. Rep. 2015, 3.
  17. Koizumi, M.; Ueda, K.; Niimura, F.; Nishiyama, A.; Yanagita, M.; Saito, A.; Pastan, I.; Fujita, T.; Fukagawa, M.; Matsusaka, T. Podocyte Injury Augments Intrarenal Angiotensin II Generation and Sodium Retention in a Megalin-Dependent Manner. Hypertension 2019, 74, 509–517.
  18. Storm, T.; Christensen, E.I.; Christensen, J.N.; Kjaergaard, T.; Uldbjerg, N.; Larsen, A.; Honore, B.; Madsen, M. Megalin Is Predominantly Observed in Vesicular Structures in First and Third Trimester Cytotrophoblasts of the Human Placenta. J. Histochem. Cytochem. 2016, 64, 769–784.
  19. Gleixner, E.M.; Canaud, G.; Hermle, T.; Guida, M.C.; Kretz, O.; Helmstadter, M.; Huber, T.B.; Eimer, S.; Terzi, F.; Simons, M. V-ATPase/mTOR signaling regulates megalin-mediated apical endocytosis. Cell Rep. 2014, 8, 10–19.
  20. Hastie, R.; Bergman, L.; Cluver, C.A.; Wikman, A.; Hannan, N.J.; Walker, S.P.; Wikstrom, A.K.; Tong, S.; Hesselman, S. Proton Pump Inhibitors and Preeclampsia Risk Among 157,720 Women. Hypertension 2019, 73, 1097–1103.
  21. Saleh, L.; Samantar, R.; Garrelds, I.M.; van den Meiracker, A.H.; Visser, W.; Danser, A.H.J. Low Soluble Fms-Like Tyrosine Kinase-1, Endoglin, and Endothelin-1 Levels in Women With Confirmed or Suspected Preeclampsia Using Proton Pump Inhibitors. Hypertension 2017, 70, 594–600.
  22. Zhou, C.C.; Ahmad, S.; Mi, T.; Xia, L.; Abbasi, S.; Hewett, P.W.; Sun, C.; Ahmed, A.; Kellems, R.E.; Xia, Y. Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. Circ. Res. 2007, 100, 88–95.
  23. Spugnini, E.P.; Citro, G.; Fais, S. Proton pump inhibitors as anti vacuolar-ATPases drugs: A novel anticancer strategy. J. Exp. Clin. Cancer Res. 2010, 29, 44.
  24. Sabolic, I.; Brown, D.; Verbavatz, J.M.; Kleinman, J. H(+)-ATPases of renal cortical and medullary endosomes are differentially sensitive to Sch-28080 and omeprazole. Am. J. Physiol. 1994, 266, F868–F877.
  25. Onda, K.; Tong, S.; Beard, S.; Binder, N.; Muto, M.; Senadheera, S.N.; Parry, L.; Dilworth, M.; Renshall, L.; Brownfoot, F.; et al. Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction. Hypertension 2017, 69, 457–468.
  26. Sun, Y.; Goes Martini, A.; Janssen, M.J.; Garrelds, I.M.; Masereeuw, R.; Lu, X.; Danser, A.H.J. Megalin: A Novel Endocytic Receptor for Prorenin and Renin. Hypertension 2020, 75, 1242–1250.
  27. Poisner, A.M. Regulation of utero-placental prorenin. Adv. Exp. Med. Biol. 1995, 377, 411–426.
  28. Shah, D.M.; Banu, J.M.; Chirgwin, J.M.; Tekmal, R.R. Reproductive tissue renin gene expression in preeclampsia. Hypertens. Pregnancy 2000, 19, 341–351.
  29. Anton, L.; Brosnihan, K.B. Systemic and uteroplacental renin--angiotensin system in normal and pre-eclamptic pregnancies. Ther. Adv. Cardiovasc. Dis. 2008, 2, 349–362.
  30. Anton, L.; Merrill, D.C.; Neves, L.A.; Stovall, K.; Gallagher, P.E.; Diz, D.I.; Moorefield, C.; Gruver, C.; Ferrario, C.M.; Brosnihan, K.B. Activation of local chorionic villi angiotensin II levels but not angiotensin (1-7) in preeclampsia. Hypertension 2008, 51, 1066–1072.
  31. Anton, L.; Merrill, D.C.; Neves, L.A.; Diz, D.I.; Corthorn, J.; Valdes, G.; Stovall, K.; Gallagher, P.E.; Moorefield, C.; Gruver, C.; et al. The uterine placental bed Renin-Angiotensin system in normal and preeclamptic pregnancy. Endocrinology 2009, 150, 4316–4325.
  32. Li, C.; Ansari, R.; Yu, Z.; Shah, D. Definitive molecular evidence of renin-angiotensin system in human uterine decidual cells. Hypertension 2000, 36, 159–164.
  33. Nonn, O.; Fischer, C.; Geisberger, S.; El-Heliebi, A.; Kroneis, T.; Forstner, D.; Desoye, G.; Staff, A.C.; Sugulle, M.; Dechend, R.; et al. Maternal Angiotensin Increases Placental Leptin in Early Gestation via an Alternative Renin-Angiotensin System Pathway: Suggesting a Link to Preeclampsia. Hypertension 2021, 77, 1723–1736.
  34. Takimoto, E.; Ishida, J.; Sugiyama, F.; Horiguchi, H.; Murakami, K.; Fukamizu, A. Hypertension induced in pregnant mice by placental renin and maternal angiotensinogen. Science 1996, 274, 995–998.
  35. Haase, N.; Foster, D.J.; Cunningham, M.W.; Bercher, J.; Nguyen, T.; Shulga-Morskaya, S.; Milstein, S.; Shaikh, S.; Rollins, J.; Golic, M.; et al. RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models. J. Clin. Invest. 2020, 130, 2928–2942.
  36. Lenz, T.; James, G.D.; Laragh, J.H.; Sealey, J.E. Prorenin secretion from human placenta perfused in vitro. Am. J. Physiol. 1991, 260, E876–E882.
  37. Lenz, T. Release of prorenin and placental hormones from superfused minced chorion laeve. Acta Obstet. Gynecol. Scand. 1997, 76, 903–906.
  38. Ye, F.; Wang, Y.; Wu, C.; Howatt, D.A.; Wu, C.H.; Balakrishnan, A.; Mullick, A.E.; Graham, M.J.; Danser, A.H.J.; Wang, J.; et al. Angiotensinogen and Megalin Interactions Contribute to Atherosclerosis-Brief Report. Arterioscler. Thromb. Vasc. Biol. 2019, 39, 150–155.
  39. Zygmunt, M.; McKinnon, T.; Herr, F.; Lala, P.K.; Han, V.K. HCG increases trophoblast migration in vitro via the insulin-like growth factor-II/mannose-6 phosphate receptor. Mol. Hum. Reprod. 2005, 11, 261–267.
  40. Burke, S.D.; Zsengeller, Z.K.; Khankin, E.V.; Lo, A.S.; Rajakumar, A.; DuPont, J.J.; McCurley, A.; Moss, M.E.; Zhang, D.; Clark, C.D.; et al. Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia. J. Clin. Invest. 2016, 126, 2561–2574.
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to :
View Times: 484
Revisions: 2 times (View History)
Update Date: 11 Nov 2021
Video Production Service