{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T08:09:46Z","timestamp":1762330186779,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tokyo NODAI Doctoral Research Grant Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Preeclampsia (PE) is characterized by maternal hypertension accompanied with multi-organ dysfunction, such as maternal hepatic and renal dysfunction. Abnormal placental conditions may play a key role in regulating maternal organ function by promoting systemic inflammation. This study aimed to test the hypothesis that placenta-derived secretions contribute to hepatic and renal injury through interorgan communication using a PE-like mouse model. Pregnant mice were infused with angiotensin II (Ang II) from gestational day (GD) 12 (GD1 defined as the day of plug detection). Ang II infusion induced maternal hypertension, as well as liver injury (elevated serum amyloid A [SAA] secretion and alanine aminotransferase levels) and kidney injury (tubular damage with KIM-1 protein expression and immune cell infiltration). Treatment with placental-conditioned medium (CM) from Ang II-infused mice, but not from the control mice, stimulated SAA expression in liver cells. On the other hand, the effects of placental-CM from both the control and Ang II groups on kidney tubular cells were comparable. These findings suggest that placenta-derived secretions in the Ang II-induced PE-like phenotype specifically promote excessive SAA production in the liver. Furthermore, SAA administration in pregnant mice did not cause tubular injury but did promote renal immune cell infiltration, indicating that elevated hepatic SAA levels may contribute to maternal kidney inflammation. Taken together, these results suggest the presence of an in vivo organ network involving the placenta, liver, and kidneys during pregnancy, where dysfunction in one organ may exacerbate the pathogenesis of PE.<\/jats:p>","DOI":"10.3390\/ijms262110737","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T07:58:05Z","timestamp":1762329485000},"page":"10737","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Placenta-Derived Secretions Promote Liver Dysfunction, and Hepatic Serum Amyloid A Mediates Kidney Inflammatory Response in a Preeclampsia-like Mouse Model"],"prefix":"10.3390","volume":"26","author":[{"given":"Ren","family":"Ozawa","sequence":"first","affiliation":[{"name":"Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, 243-0034, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sae","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, 243-0034, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayaka","family":"Shirota","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, 243-0034, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shota","family":"Nomura","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, 243-0034, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3360-3185","authenticated-orcid":false,"given":"Takanori","family":"Komada","sequence":"additional","affiliation":[{"name":"Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, 329-0498, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2716-7532","authenticated-orcid":false,"given":"Masafumi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, 329-0498, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7238-8997","authenticated-orcid":false,"given":"Hisataka","family":"Iwata","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, 243-0034, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koumei","family":"Shirasuna","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Atsugi, 243-0034, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dimitriadis, E., Rolnik, D.L., Zhou, W., Estrada-Gutierrez, G., Koga, K., Francisco, R.P., Whitehead, C., Hyett, J., da Silva Costa, F., and Nicolaides, K. (2023). Pre-eclampsia. Nat. Rev. Dis. Primers, 9.","DOI":"10.1038\/s41572-023-00417-6"},{"key":"ref_2","first-page":"117","article-title":"Serum Amyloid A Levels Are Increased in Pre-Eclampsia","volume":"64","author":"Karabulut","year":"2006","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S819","DOI":"10.1016\/j.ajog.2020.08.108","article-title":"Proteinuria during pregnancy: Definition, pathophysiology, methodology, and clinical significance","volume":"226","author":"Bartal","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Vigil-De Gracia, P., Vargas, C., S\u00e1nchez, J., and Collantes-Cubas, J. (2023). Preeclampsia: Narrative review for clinical use. Heliyon, 9.","DOI":"10.1016\/j.heliyon.2023.e14187"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1172\/JCI17189","article-title":"Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia","volume":"111","author":"Maynard","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41581-022-00670-0","article-title":"The role of immune cells and mediators in preeclampsia","volume":"19","author":"Deer","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Schuster, J., Cheng, S.B., Padbury, J., and Sharma, S. (2021). Placental extracellular vesicles and pre-eclampsia. Am. J. Reprod. Immunol., 85.","DOI":"10.1111\/aji.13297"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1681\/ASN.2009010061","article-title":"The soluble VEGF receptor sFlt1 contributes to endothelial dysfunction in CKD","volume":"20","author":"Reuter","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"41","DOI":"10.3109\/10641955.2013.835820","article-title":"Hypertension, inflammation and T lymphocytes are increased in a rat model of HELLP syndrome","volume":"33","author":"Wallace","year":"2014","journal-title":"Hypertens. Pregnancy"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.biopha.2018.10.082","article-title":"Preeclampsia: A close look at renal dysfunction","volume":"109","author":"Ardalan","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sack, G.H. (2018). Serum amyloid A\u2014A review. Mol. Med., 24.","DOI":"10.1186\/s10020-018-0047-0"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Fosheim, I.K., Jacobsen, D.P., Sugulle, M., Alnaes-Katjavivi, P., Fjeldstad, H.E.S., Ueland, T., Lekva, T., and Staff, A.C. (2023). Serum amyloid A1 and pregnancy zone protein in pregnancy complications and correlation with markers of placental dysfunction. Am. J. Obstet. Gynecol. MFM, 5.","DOI":"10.1016\/j.ajogmf.2022.100794"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ozawa, R., Iwata, H., Kuwayama, T., and Shirasuna, K. (2024). Maternal hypertensive condition alters adipose tissue function and blood pressure sensitivity in offspring. Biochem. Biophys. Res. Commun., 707.","DOI":"10.1016\/j.bbrc.2024.149617"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Liu, W., Baker, S.S., Baker, R.D., Nowak, N.J., and Zhu, L. (2011). Upregulation of hemoglobin expression by oxidative stress in hepatocytes and its implication in nonalcoholic steatohepatitis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024363"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"565","DOI":"10.3109\/1354750X.2015.1123354","article-title":"The potential of lipocalin-2\/NGAL as biomarker for inflammatory and metabolic diseases","volume":"20","author":"Abella","year":"2015","journal-title":"Biomarkers"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Asimakopoulou, A., Weiskirchen, S., and Weiskirchen, R. (2016). Lipocalin 2 (LCN2) expression in hepatic malfunction and therapy. Front. Physiol., 7.","DOI":"10.3389\/fphys.2016.00430"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Nowicka, A.A., Gomu\u0142kiewicz, A., Serafi\u0144ska, S., Simon, K.A., and Dzi\u0119giel, P. (2025). Metallothioneins in the Pathogenesis of Liver Diseases: A Review. Int. J. Hepatol., 2025.","DOI":"10.1155\/ijh\/8880889"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0014-5793(03)00217-5","article-title":"DMBT1, a regulator of mucosal homeostasis through the linking of mucosal defense and regeneration?","volume":"540","author":"Kang","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/S0002-9440(10)64395-7","article-title":"Heterogeneity of ductular reactions in adult rat and human liver revealed by novel expression of deleted in malignant brain tumor 1","volume":"161","author":"Bisgaard","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1189\/jlb.1109756","article-title":"Mouse CD84 is a pan-leukocyte cell-surface molecule that modulates LPS-induced cytokine secretion by macrophages","volume":"88","author":"Sintes","year":"2010","journal-title":"J. Leukoc. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/labinvest.2009.148","article-title":"Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions","volume":"90","author":"Ichii","year":"2010","journal-title":"Lab. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5239","DOI":"10.1038\/s44319-024-00296-2","article-title":"The Dectin-1 and Dectin-2 clusters: C-type lectin receptors with fundamental roles in immunity","volume":"25","author":"Malamud","year":"2024","journal-title":"EMBO Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/s41586-018-0615-z","article-title":"LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration","volume":"562","author":"Deng","year":"2018","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Le\u015bniak, W., and Filipek, A. (2023). S100A6 protein\u2014Expression and function in norm and pathology. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021341"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1046\/j.1523-1755.2002.00433.x","article-title":"Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury","volume":"62","author":"Han","year":"2002","journal-title":"Kidney Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1172\/JCI34487","article-title":"Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells","volume":"118","author":"Ichimura","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1161\/ATVBAHA.114.304776","article-title":"Deficiency of Endogenous Acute-Phase Serum Amyloid A Protects apoE\u2212\/\u2212 Mice From Angiotensin II\u2013Induced Abdominal Aortic Aneurysm Formation","volume":"35","author":"Webb","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1016\/j.ajpath.2015.06.016","article-title":"Hepatic expression of serum amyloid A1 is induced by traumatic brain injury and modulated by telmisartan","volume":"185","author":"Villapol","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1681\/ASN.2008060628","article-title":"IL-6 and serum amyloid A synergy mediates angiotensin II-induced muscle wasting","volume":"20","author":"Zhang","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.bbrc.2003.12.096","article-title":"IL-6 plays a critical role in the synergistic induction of human serum amyloid A (SAA) gene when stimulated with proinflammatory cytokines as analyzed with an SAA isoform real-time quantitative RT-PCR assay system","volume":"314","author":"Hagihara","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1111\/j.1365-2443.2005.00900.x","article-title":"Essential role of STAT3 in cytokine-driven NF-\u03baB-mediated serum amyloid A gene expression","volume":"10","author":"Hagihara","year":"2005","journal-title":"Genes Cells"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1210\/en.2015-1408","article-title":"NLRP3 Deficiency Improves Angiotensin II-Induced Hypertension But Not Fetal Growth Restriction During Pregnancy","volume":"156","author":"Shirasuna","year":"2015","journal-title":"Endocrinology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1053\/j.gastro.2003.11.054","article-title":"Placenta-derived CD95 ligand causes liver damage in hemolysis, elevated liver enzymes, and low platelet count syndrome","volume":"126","author":"Strand","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Oe, Y., Ko, M., Fushima, T., Sato, E., Karumanchi, S.A., Sato, H., Sugawara, J., Ito, S., and Takahashi, N. (2018). Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase. Sci. Rep., 8.","DOI":"10.1038\/s41598-017-18260-7"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"F1009","DOI":"10.1152\/ajprenal.00257.2015","article-title":"Increased urinary levels of podocyte glycoproteins, matrix metallopeptidases, inflammatory cytokines, and kidney injury biomarkers in women with preeclampsia","volume":"309","author":"Wang","year":"2015","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wang, Y., Gu, Y., Gu, X., Cooper, D.B., and Lewis, D.F. (2023). Evidence of kidney injury in preeclampsia: Increased maternal and urinary levels of NGAL and KIM-1 and their enhanced expression in proximal tubule epithelial cells. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1130112"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"H1345","DOI":"10.1152\/ajpheart.00096.2019","article-title":"Role of T-cell activation in salt-sensitive hypertension","volume":"316","author":"Ren","year":"2019","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Peter, J.K., Umene, R., Wu, C.H., Nakamura, Y., Washimine, N., Yamamoto, R., Ngugi, C., Linge, K., Kweri, J.K., and Inoue, T. (2024). Renal macrophages induce hypertension and kidney fibrosis in Angiotensin II salt mice model. Biochem. Biophys. Res. Commun., 715.","DOI":"10.1016\/j.bbrc.2024.149997"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1161\/CIRCRESAHA.123.323897","article-title":"NETosis Drives Blood Pressure Elevation and Vascular Dysfunction in Hypertension","volume":"134","author":"Krishnan","year":"2024","journal-title":"Circ. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1093\/ckj\/sfac060","article-title":"Kidney\u2013placenta crosstalk in health and disease","volume":"15","author":"Capalbo","year":"2022","journal-title":"Clin. Kidney J."},{"key":"ref_41","unstructured":"Fukazawa, K., and Lee, H.T. (2013). Updates on hepato-renal syndrome. J. Anesth. Clin. Res., 4."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.cytogfr.2015.12.010","article-title":"The cytokine-serum amyloid A-chemokine network","volume":"30","author":"Gouwy","year":"2016","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Gaiser, A.-K., Bauer, S., Ruez, S., Holzmann, K., F\u00e4ndrich, M., Syrovets, T., and Simmet, T. (2021). Serum amyloid A1 induces classically activated macrophages: A role for enhanced fibril formation. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.691155"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Gathiram, P., and Moodley, J. (2020). The role of the renin-angiotensin-aldosterone system in preeclampsia: A review. Curr. Hypertens. Rep., 22.","DOI":"10.1007\/s11906-020-01098-2"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1126\/science.274.5289.995","article-title":"Hypertension induced in pregnant mice by placental renin and maternal angiotensinogen","volume":"274","author":"Takimoto","year":"1996","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1172\/JCI83918","article-title":"Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia","volume":"126","author":"Burke","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1111\/j.1349-7006.1991.tb01803.x","article-title":"A tubule cell line established from transgenic mice harboring temperature-sensitive simian virus 40 large T-antigen gene","volume":"82","author":"Yanai","year":"1991","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_48","first-page":"701","article-title":"Establishment of a clone of mouse liver cells from a single isolated cell","volume":"18","author":"Hobbs","year":"1957","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Taru, M., Katoh, T., Koshimizu, K., Kuribayashi, S., Miura, R., Hamano, S., and Shirasuna, K. (2024). Inflammatory uterine microenvironment in long-term infertility repeat breeder cows compared with normal fertile cows. Vet. Anim. Sci., 25.","DOI":"10.1016\/j.vas.2024.100369"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Komada, T., Usui, F., Kawashima, A., Kimura, H., Karasawa, T., Inoue, Y., Kobayashi, M., Mizushina, Y., Kasahara, T., and Taniguchi, S. (2015). Role of NLRP3 Inflammasomes for Rhabdomyolysis-induced Acute Kidney Injury. Sci. Rep., 5.","DOI":"10.1038\/srep10901"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1038\/s41418-022-01033-9","article-title":"dsDNA-induced AIM2 pyroptosis halts aberrant inflammation during rhabdomyolysis-induced acute kidney injury","volume":"29","author":"Baatarjav","year":"2022","journal-title":"Cell Death Differ."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10737\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T08:02:56Z","timestamp":1762329776000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10737"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":51,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110737"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110737","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]}}}