Title

Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension

Authors

Nian Cao, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Cong Lan, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Caiyu Chen, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Zaicheng Xu, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Hao Luo, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Shuo Zheng, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Xue Gong, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Hongmei Ren, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Zhuxin Li, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Shuang Qu, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Cheng Yu, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Jining Yang, Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine (J. Yang).
Pedro A. Jose, Division of Renal Diseases and Hypertension, The George Washington University School of Medicine and Health Sciences, Washington, DC (P.A.J.).
Gengze Wu, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Cuimei Hu, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Junyi Yu, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).
Chunyu Zeng, Department of Cardiology, Daping Hospital, The Third Military Medical University (Army Medical University), P.R. China. (N.C., C.L., C.C., Z.X., H.L., S.Z., X.G., H.R., Z.L., S.Q., C.Y., G.W., C.H., J.Yu, C.Z.).

Document Type

Journal Article

Publication Date

8-25-2022

Journal

Circulation

DOI

10.1161/CIRCULATIONAHA.122.059891

Keywords

epigenetics; hypertension; lipopolysaccharides; reactive oxygen species; receptors, mineralocorticoid

Abstract

BACKGROUND: Adverse environmental exposure during the prenatal period can lead to diseases in the offspring, including hypertension. Whether or not the hypertensive phenotype can be transgenerationally transmitted is not known. METHODS: Pregnant Sprague Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) on gestation days 6, 8, 10, and 12 to generate the prenatal LPS exposure model. Blood pressure was monitored by both telemetry and tail-cuff method. RNA sequencing was performed to analyze transcriptome alteration in the kidney of the third generation. Tempol and spironolactone were used to test the potential prevention and therapeutic effect of targeting reactive oxygen species and mineralocorticoid receptor signaling, respectively. Molecular biological experiments were performed to illustrate the mechanism of epigenetic and transcription regulation. RESULTS: Prenatal LPS exposure can impair the ability to excrete a salt load and induce hypertension from the first to the third generations, with the fourth and fifth generations, inducing salt-sensitive hypertension. Compared with control pups, the transcriptome in the kidney of the hypertensive third-generation prenatal LPS-exposed offspring have upregulation of the Ras-related C3 botulinum toxin substrate 1 () gene and activation of mineralocorticoid receptor signaling. Furthermore, we found that LPS exposure during pregnancy triggered oxidative stress that upregulated KDM3B (histone lysine demethylase 3B) in the oocytes of first-generation female rats, leading to an inheritable low level of H3K9me2 (histone H3 lysine 9 dimethylation), resulting in the transgenerational upregulation of . Based on these findings, we treated the LPS-exposed pregnant rats with the reactive oxygen species scavenger, tempol, which successfully prevented hypertension in the first-generation offspring and the transgenerational inheritance of hypertension. CONCLUSIONS: These findings show that adverse prenatal exposure induces transgenerational hypertension through an epigenetic-regulated mechanism and identify potentially preventive and therapeutic strategies for hypertension.

Department

Medicine

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