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Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway.

ABSTRACT: To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms-like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.

SUBMITTER: Dupont V

PROVIDER: S-EPMC9566901 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway.

Dupont Vincent V Berg Anders H AH Yamashita Michifumi M Huang Chengqun C Covarrubias Ambart E AE Ali Shafat S Stotland Aleksandr A Van Eyk Jennifer E JE Jim Belinda B Thadhani Ravi R Karumanchi S Ananth SA

The Journal of clinical investigation 20221017 20

To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms-like tyrosine kinase 1 (sF ...[more]

PMID: 35943814

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Project description:Preeclampsia (PE) is a life-threatening hypertensive disorder during pregnancy associated with decreased circulating aldosterone levels. However, the molecular mechanisms underlying aldosterone reduction in PE remain unidentified. Here we demonstrate that reduced circulating aldosterone levels in preeclamptic women are associated with the presence of angiotensin II type 1 receptor agonistic autoantibody and elevated soluble Fms-like tyrosine kinase-1, 2 prominent pathogenic factors in PE. Using an adoptive transfer animal model of PE, we provide in vivo evidence that the injection of IgG from women with PE, but not IgG from normotensive individuals, resulted in hypertension, proteinuria, and a reduction in aldosterone production from 1377 ± 272 pg/mL to 544 ± 92 pg/mL (P<0.05) in pregnant mice. These features were prevented by coinjection with an epitope peptide that blocks antibody-mediated angiotensin type 1 receptor activation. In contrast, injection of IgG from preeclamptic women into nonpregnant mice induced aldosterone levels from 213 ± 24 pg/mL to 615 ± 48 pg/mL (P<0.05). These results indicate that maternal circulating autoantibody in preeclamptic women is a detrimental factor causing decreased aldosterone production via angiotensin type 1 receptor activation in a pregnancy-dependent manner. Next, we found that circulating soluble Fms-like tyrosine kinase-1 was only induced in autoantibody-injected pregnant mice but not nonpregnant mice. As such, we further observed vascular impairment in adrenal glands of pregnant mice. Finally, we demonstrated that infusion of vascular endothelial growth factor(121) attenuated autoantibody-induced adrenal gland vascular impairment resulting in a recovery in circulating aldosterone (from 544 ± 92 to 1110 ± 269 pg/mL; P<0.05). Overall, we revealed that angiotensin II type 1 receptor agonistic autoantibody-induced soluble Fms-like tyrosine kinase-1 elevation is a novel pathogenic mechanism underlying decreased aldosterone production in PE.

Project description:Preeclampsia is a maternal hypertensive disorder that affects up to 1 out of 12 pregnancies worldwide. It is characterized by proteinuria, endothelial dysfunction, and elevated levels of the soluble form of the vascular endothelial growth factor receptor-1 (VEGFR-1, known as sFlt-1). sFlt-1 effects are mediated in part by decreasing VEGF signaling. The direct effects of sFlt-1 on cellular metabolism and bioenergetics in preeclampsia, have not been established. The goal of this study was to evaluate whether sFlt-1 causes mitochondrial dysfunction leading to disruption of normal functioning in endothelial and placental cells in preeclampsia. Endothelial cells (ECs) and first-trimester trophoblast (HTR-8/SVneo) were treated with serum from preeclamptic women rich in sFlt-1 or with the recombinant protein. sFlt-1, dose-dependently inhibited ECs respiration and acidification rates indicating a metabolic phenotype switch enhancing glycolytic flux. HTR-8/SVneo displayed a strong basal glycolytic metabolism, remaining less sensitive to sFlt-1-induced mitochondrial impairment. Moreover, results obtained in ECs exposed to serum from preeclamptic subjects demonstrated that increased sFlt-1 leads to metabolic perturbations accountable for mitochondrial dysfunction observed in preeclampsia. sFlt-1 exacerbated mitochondrial reactive oxygen species (ROS) formation and mitochondrial membrane potential dissipation in ECs and trophoblasts exposed to serum from preeclamptic women. Forcing oxidative metabolism by culturing cells in galactose media, further sensitized cells to sFlt-1. This approach let us establish that sFlt-1 targets mitochondrial function in ECs. Effects of sFlt-1 on HTR-8/SVneo cells metabolism were amplified in galactose, demonstrating that sFlt-1 only target cells that rely mainly on oxidative metabolism. Together, our results establish the early metabolic perturbations induced by sFlt-1 and the resulting endothelial and mitochondrial dysfunction in preeclampsia.

Dataset Information

Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway.

Publications

Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway.

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