Search

Introduction: Preeclamptic patients, both lean and obese, present with elevated leptin levels which are associated with the development of maternal endothelial dysfunction and adverse fetal outcomes, such as growth restriction, leading to low birth weight. Recent studies in pregnant mice demonstrate that mid-late gestation leptin infusion induces clinical characteristics of preeclampsia, including elevated maternal blood pressure, maternal endothelial dysfunction and fetal growth restriction. However, whether leptin triggers placental stress responses that contribute to adverse fetal outcomes as in preeclampsia is unknown., Methods: In the current study we measured the expression of proteins involved in the endoplasmic reticulum (UPR er ) and mitochondrial (UPR mt ) unfolded protein responses in placentas of wild-type sham normal pregnant and leptin-infused preeclamptic mice., Results: The data show that mid-late gestation leptin infusion induced activation of indices of placental UPR er and UPR mt , while reducing placental repair mechanisms to UPR mt in preeclamptic mice. Mid-late gestation infusion with leptin upregulated markers of placental oxidative stress, reduced the placental expression levels of mitochondrial electron transport chain complexes I and II and increased the expression of placental endothelin-1 (ET-1) in preeclamptic mice. The leptin-induced activation of several placental UPR mt markers as well as ET-1 levels correlated with fetal growth restriction and impaired maternal endothelial function in preeclamptic mice., Discussion: Collectively, these data indicate that elevated levels of leptin in mid-late pregnancy in mice promote placental stress responses, akin to those in pregnant women with preeclampsia., Competing Interests: Declaration of competing interest This work was supported by NIH1R01HL169576, 4R00HL146948 to JLF, AHA24PRE1196923 to DM and by the British Heart Foundation PG/14/5/30,547 to DAG. This work was partially supported by Department of Obstetrics and Gynecology, Toho University Faculty of Medicine., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

One of the initiating events in preeclampsia (PE) is placental ischemia. Rodent models of placental ischemia do not present with vascular endothelial dysfunction, a hallmark of PE. We previously demonstrated a role for leptin in endothelial dysfunction in pregnancy in the absence of placental ischemia. We hypothesized that placental ischemia requires hyperleptinemia and endothelial mineralocorticoid receptor (ECMR) expression to induce PE-associated endothelial dysfunction in pregnant mice. We induced placental ischemia via the reduced uterine perfusion pressure (RUPP) procedure in pregnant ECMR-intact ( ECMR +/+ ) and ECMR deletion ( ECMR -/- ) mice at gestational day (GD) 13 . ECMR +/+ RUPP pregnant mice also received concurrent leptin infusion via miniosmotic pump (0.9 mg/kg/day). RUPP increased blood pressure via radiotelemetry and decreased fetal growth in ECMR +/+ pregnant mice. Both increases in blood pressure and reduced fetal growth were abolished in RUPP ECMR -/- mice. Placental ischemia did not decrease endothelial-dependent relaxation to acetylcholine (ACh) but increased phenylephrine (Phe) contraction in mesenteric arteries of pregnant mice, which was ablated by ECMR deletion. Addition of leptin to RUPP mice significantly reduced ACh relaxation in ECMR +/+ pregnant mice, accompanied by an increase in soluble FMS-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PLGF) ratio. In conclusion, our data indicate that high leptin levels drive endothelial dysfunction in PE and that ECMR is required for clinical characteristics of hypertension and fetal growth restriction in placental ischemia PE. Collectively, we show that both ECMR and leptin play a role to mediate PE. NEW & NOTEWORTHY Leptin is a key feature of preeclampsia that initiates vascular endothelial dysfunction in preeclampsia characterized by placental ischemia. Endothelial mineralocorticoid receptor (ECMR) deletion in placental ischemia protects pregnant mice from elevations in blood pressure and fetal growth restriction in pregnancy. Increases in leptin production mediate the key pathological feature of endothelial dysfunction in preeclampsia in rodents. ECMR activation contributes to the increase in blood pressure and fetal growth restriction in preeclampsia.

Sarcopenia poses a significant challenge to public health and can severely impact the quality of life of aging populations. Despite extensive efforts to study muscle degeneration using traditional animal models, there is still a lack of effective diagnostic tools, precise biomarkers, and treatments for sarcopenia. Zebrafish models have emerged as powerful tools in biomedical research, providing unique insights into age-related muscle disorders like sarcopenia. The advantages of using zebrafish models include their rapid growth outside of the embryo, optical transparency during early developmental stages, high reproductive potential, ease of husbandry, compact size, and genetic tractability. By deepening our understanding of the molecular processes underlying sarcopenia, we may develop novel diagnostic tools and effective treatments that can improve the lives of aging individuals affected by this condition. This review aims to explore the unique advantages of zebrafish as a model for sarcopenia research, highlight recent breakthroughs, outline potential avenues for future investigations, and emphasize the distinctive contributions that zebrafish models offer. Our research endeavors to contribute significantly to address the urgent need for practical solutions to reduce the impact of sarcopenia on aging populations, ultimately striving to enhance the quality of life for individuals affected by this condition.

Renal function increases in pregnancy due to the significant hemodynamic demands of plasma volume expansion and the growing feto-placental unit. Therefore, compromised renal function increases the risk for adverse outcomes for pregnant women and their offspring. Acute kidney injury (AKI), or sudden loss of kidney function, is a significant event that requires aggressive clinical management. An AKI event in pregnancy, or in the postpartum period, significantly increases the risk of adverse pregnancy events and fetal and maternal mortality. At present, there are significant clinical challenges to the identification, diagnosis, and management of pregnancy-associated AKI due to changing hemodynamics in pregnancy that alter baseline values and to treatment limitations in pregnancy. Emerging data indicate that patients that are considered clinically recovered following AKI, which is currently assessed primarily by return of plasma creatinine levels to normal, maintain risk of long-term complications indicating that current recovery criteria mask the detection of subclinical renal damage. In association, recent large-scale clinical cohorts indicate that a history of AKI predisposes women to adverse pregnancy events even years after the patient is considered recovered from AKI. Mechanisms via which women develop AKI in pregnancy, or develop adverse pregnancy events post-AKI, are poorly understood and require significant study to better prevent and treat AKI in women. © 2023 American Physiological Society. Compr Physiol 13:4869-4878, 2023., (Copyright © 2023 American Physiological Society. All rights reserved.)

Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte hypertrophy and podocyte loss during the pathogenesis of focal segmental glomerulosclerosis (FSGS) remains undefined. Here, we examined rpS6 phosphorylation levels in kidney biopsy specimens from patients with FSGS and in podocytes from mouse kidneys with Adriamycin-induced FSGS. Using genetic and pharmacologic approaches in the mouse model of FSGS, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS. Phosphorylated rpS6 was found to be markedly increased in the podocytes of patients with FSGS and Adriamycin-induced FSGS mice. Genetic deletion of the Tuberous sclerosis 1 gene in kidney glomerular podocytes activated mammalian target of rapamycin complex 1 signaling to rpS6 phosphorylation, resulting in podocyte hypertrophy and pathologic features similar to those of patients with FSGS including podocyte loss, leading to segmental glomerulosclerosis. Since protein phosphatase 1 is known to negatively regulate rpS6 phosphorylation, treatment with an inhibitor increased phospho-rpS6 levels, promoted podocyte hypertrophy and exacerbated formation of FSGS lesions. Importantly, blocking rpS6 phosphorylation (either by generating congenic rpS6 knock-in mice expressing non-phosphorylatable rpS6 or by inhibiting ribosomal protein S6 kinase 1-mediated rpS6 phosphorylation with an inhibitor) significantly blunted podocyte hypertrophy, inhibited podocyte loss, and attenuated formation of FSGS lesions. Thus, our study provides genetic and pharmacologic evidence indicating that specifically targeting rpS6 phosphorylation can attenuate the development of FSGS lesions by inhibiting podocyte hypertrophy and associated podocyte depletion., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)