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The Inhibition of Protein Kinase C ? Contributes to the Pathogenesis of Preeclampsia by Activating Autophagy.

ABSTRACT: BACKGROUND:Preeclampsia is a devastating hypertensive disorder of pregnancy with unknown mechanism. Recent studies have considered abnormal autophagy as a new cellular mechanism for this disorder, while little is known about how autophagy is specifically involved and what factors are implicated. Here, we report a previously unrecognized preeclampsia-associated autophagic regulator, PKC?, that is involved in placental angiogenesis. METHODS:PKC? levels were evaluated by quantitative real-time PCR, western blotting, immunofluorescence and by the analysis of public data. The autophagy-regulating role of PKC? inhibition in preeclampsia pathogenesis was studied in a mouse model, and in human umbilical vein endothelial cells (HUVECs) and human choriocarcinoma cells (JEG-3). FINDINGS:PKC? was significantly downregulated in human preeclamptic placentas. In a mouse model, the selective inhibition of PKC? by Ruboxistaurin was sufficient to induce preeclampsia-like symptoms, accompanied by excessive autophagic flux and a disruption in the balance of pro- and anti-angiogenic factors in mouse placentas. In contrast, autophagic inhibition by 3-methyladenine partially normalized hypertension, proteinuria and placental angiogenic imbalance in PKC?-inhibited mice. Our in vitro experiments demonstrated that PKC? inhibition activated autophagy, thus blocking VEGFA-induced HUVEC tube formation and resulting in the significant upregulation of sFLT1 and downregulation of VEGFA in JEG-3 cells. INTERPRETATION:These data support a novel model in which autophagic activation due to PKC? inhibition leads to the impairment of angiogenesis and eventually results in preeclampsia. FUNDING:Shanghai Key Program of Clinical Science and Technology Innovation, National Natural Science Foundation of China and Shanghai Medical Center of Key Programs for Female Reproductive Diseases.

SUBMITTER: Zhao H

PROVIDER: S-EPMC7298655 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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The Inhibition of Protein Kinase C β Contributes to the Pathogenesis of Preeclampsia by Activating Autophagy.

Zhao Huanqiang H Gong Lili L Wu Suwen S Jing Tianrui T Xiao Xirong X Cui Yutong Y Xu Huangfang H Lu Huiqing H Tang Yao Y Zhang Jin J Zhou Qiongjie Q Ma Duan D Li Xiaotian X

EBioMedicine 20200613

<h4>Background</h4>Preeclampsia is a devastating hypertensive disorder of pregnancy with unknown mechanism. Recent studies have considered abnormal autophagy as a new cellular mechanism for this disorder, while little is known about how autophagy is specifically involved and what factors are implicated. Here, we report a previously unrecognized preeclampsia-associated autophagic regulator, PKCβ, that is involved in placental angiogenesis.<h4>Methods</h4>PKCβ levels were evaluated by quantitative ...[more]

PMID: 32544612

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Project description:Preeclampsia (PE) is a prevalent life-threatening hypertensive disorder of pregnancy associated with increased complement activation. However, the causative factors and pathogenic role of increased complement activation in PE are largely unidentified. Here we report that a circulating maternal autoantibody, the angiotensin II type 1 receptor agonistic autoantibody, which emerged recently as a potential pathogenic contributor to PE, stimulates deposition of complement C3 in placentas and kidneys of pregnant mice via angiotensin II type 1 receptor activation. Next, we provide in vivo evidence that selectively interfering with C3a signaling by a complement C3a receptor-specific antagonist significantly reduces hypertension from 167±7 to 143±5 mm Hg and proteinuria from 223.5±7.5 to 78.8±14.0 ?g of albumin per milligram creatinine (both P<0.05) in angiotensin II type 1 receptor agonistic autoantibody-injected pregnant mice. In addition, we demonstrated that complement C3a receptor antagonist significantly inhibited autoantibody-induced circulating soluble fms-like tyrosine kinase 1, a known antiangiogenic protein associated with PE, and reduced small placental size with impaired angiogenesis and intrauterine growth restriction. Similarly, in humans, we demonstrate that C3 deposition is significantly elevated in the placentas of preeclamptic patients compared with normotensive controls. Lastly, we show that complement C3a receptor activation is a key mechanism underlying autoantibody-induced soluble fms-like tyrosine kinase 1 secretion and decreased angiogenesis in cultured human villous explants. Overall, we provide mouse and human evidence that angiotensin II type 1 receptor agonistic autoantibody-mediated activation contributes to elevated C3 and that complement C3a receptor signaling is a key mechanism underlying the pathogenesis of the disease. These studies are the first to link angiotensin II type 1 receptor agonistic autoantibody with complement activation and to provide important new opportunities for therapeutic intervention in PE.

Project description:Leptin plays a crucial role in regulating energy homoeostasis, neuroendocrine function, metabolism, and immune and inflammatory responses. The adipose tissue is a main source of leptin, but during pregnancy, leptin is also secreted primarily by the placenta. Circulating leptin levels peak during the second trimester of human pregnancy and fall after labor. Several studies indicated a strong association between elevated placental leptin levels and preeclampsia (PE) pathogenesis and elevated serum interleukin-6 (IL-6) levels in PE patients. Therefore, we hypothesized that a local increase in placental leptin production induces IL-6 production in Hofbauer cells (HBCs) to contribute to PE-associated inflammation. We first investigated HBCs-specific IL-6 and leptin receptor (LEPR) expression and compared their immunoreactivity in PE vs. gestational age-matched control placentas. Subsequently, we examined the in vitro regulation of IL-6 as well as the phosphorylation levels of intracellular signaling proteins STAT3, STAT5, NF-κB, and ERK1/2 by increasing recombinant human leptin concentrations (10 to 1000 ng/mL) in primary cultured HBCs. Lastly, HBC cultures were incubated with leptin ± specific inhibitors of STAT3 or STAT5, or p65 NF-κB or ERK1/2 MAPK signaling cascades to determine relevant cascade(s) involved in leptin-mediated IL-6 regulation. Immunohistochemistry revealed ~three- and ~five-fold increases in IL-6 and LEPR expression, respectively, in HBCs from PE placentas. In vitro analysis indicated that leptin treatment in HBCs stimulate IL-6 in a concentration-dependent manner both at the transcriptional and secretory levels (p < 0.05). Moreover, leptin-treated HBC cultures displayed significantly increased phosphorylation levels of STAT5, p65 NF-κB, and ERK1/2 MAPK and pre-incubation of HBCs with a specific ERK1/2 MAPK inhibitor blocked leptin-induced IL-6 expression. Our in situ results show that HBCs contribute to the pathogenesis of PE by elevating IL-6 expression, and in vitro results indicate that induction of IL-6 expression in HBCs is primarily leptin-mediated. While HBCs display an anti-inflammatory phenotype in normal placentas, elevated levels of leptin may transform HBCs into a pro-inflammatory phenotype by activating ERK1/2 MAPK to augment IL-6 expression.

Dataset Information

The Inhibition of Protein Kinase C ? Contributes to the Pathogenesis of Preeclampsia by Activating Autophagy.

Publications

The Inhibition of Protein Kinase C β Contributes to the Pathogenesis of Preeclampsia by Activating Autophagy.

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