Denise C. Cornelius

Background: Previous studies from our laboratory have shown that hyperinsulinemia and insulin resistance (IR) are elevated in obese Dahl salt-sensitive (SS) leptin receptor mutant (SS ^LepR mutant) rats compared to SS rats before puberty. Clinical studies suggest that time-restricted feeding improves insulin sensitivity and is considered beneficial in obese patients. Therefore, the current study examined whether time-restricted feeding improves IR and reduces renal injury in obese SS ^LepR mutant rats prior to puberty. Methods: Four-week-old SS and SS ^LepR mutant rats were given either ad libitum access to food for 24 hours (control) or 8 hours each day during their active phase time-restricted feeding for 4 weeks. Metabolic parameters, insulin sensitivity, renal function and injury, proximal tubular SGLT2 expression, inflammation, and mitochondrial bioenergetics were assessed at the end of the study. Results: Body weight and food intake were significantly elevated in SS ^LepR mutant compared to SS rats, and time-restricted feeding did not affect either parameter. Fasting blood glucose levels were normal (≤120 mg/dL) in all groups. HOMA-IR (marker of IR) was significantly elevated in SS ^LepR mutant rats versus SS rats, and time-restricted feeding significantly reduced HOMA-IR only in SS ^LepR mutant rats. Proteinuria was significantly higher in SS ^LepR mutant rats vs SS rats (361±32 vs. 17±4 mg/day, respectively), and time-restricted feeding markedly reduced proteinuria in SS ^LepR mutant rats (144±19 mg/day). We observed a 2-fold increase in GFR in SS ^LepR mutant rats compared to SS rats indicating renal hyperfiltration. Time-restricted feeding prevented renal hyperfiltration in SS ^LepR mutant rats. Renal tubular sodium–glucose cotransporter 2 (SGLT2) expression was markedly increased in SS ^LepR mutant rats relative to SS rats and was notably reduced by time-restricted feeding in the SS ^LepR mutant rats. When measuring mitochondrial function, there was a tendency of OCR to be reduced in SS ^LepR mutant rats compared to SD rats, indicating impaired mitochondrial function, but time-restricted feeding significantly increased baseline OCR in SS ^LepR mutant rats. Conclusions: Overall, these data suggest that time-restricted feeding reduces proteinuria by potentially improving insulin sensitivity and tubular mitochondrial function indicating TRF could be of great potential in obese children with early signs of renal injury.

CLINICAL PROBLEM: Preeclampsia is a heterogeneous hypertensive disorder of pregnancy characterized by new-onset hypertension and end-organ dysfunction, affecting 5% to 10% of pregnancies globally. It is associated with significant maternal and fetal morbidity and mortality, and delivery remains the only definitive treatment. Understanding the underlying mechanisms is essential for the development of effective therapies. RECOMMENDATIONS: Given the heterogeneity of preeclampsia and the absence of a single experimental model that fully recapitulates the human disease, the purpose of this review is to evaluate current animal models of preeclampsia according to the pathophysiological mechanisms they represent. We discuss the strengths, limitations, and translational relevance of these models, identify gaps in the existing experimental framework, and highlight opportunities for future model development and therapeutic discovery. SUMMARY: Current models reproduce distinct features of preeclampsia, including abnormal placentation, placental ischemia, angiogenic imbalance, endothelial dysfunction, immune activation, and metabolic dysregulation. Despite mechanistic insights, translational success has been limited. Future progress will depend on mechanism-driven model selections, development of models that better capture early placentation defects and disease heterogeneity, multi-hit approaches, including the incorporation of maternal comorbidities, and integration of human-relevant experimental systems to improve clinical translation.

Preeclampsia (PE), new-onset hypertension during pregnancy, is associated with chronic inflammation both in the placenta and systemically. PE is characterized by placental ischemia, which then results in the production and release of anti-angiogenic factors and inflammatory mediators. Inflammation in PE leads to placental, renal, and vascular damage, which contribute to the phenotype of hypertension and organ dysfunction during pregnancy. T cells, B cells, Natural Killer cells, and macrophages have all been shown to play a role in the inflammation present in the disease. T helper cells contribute to the chronic inflammation in PE. They also activate B cells, which produce agonistic autoantibodies against the angiotensin II type 1 receptor. Natural Killer cells are activated in PE and shift away from decidual Natural killer cells, which produce angiogenic factors, and toward cytotoxic Natural Killer cells, which contribute to tissue damage. Macrophages are polarized towards proinflammatory subtypes and contribute to tissue damage and inflammatory signaling in PE patients. As the immune system plays a role in the pathophysiology of the disease, it may be a potential target for therapeutic intervention to improve maternal and fetal outcomes during and following a PE pregnancy.

Polycystic ovary syndrome (PCOS) is associated with a high prevalence of insulin resistance (IR) and obesity. Adiponectin, an insulin-sensitizing hormone, is reduced in PCOS and inversely correlated with IR and obesity. This study tested whether androgens reduce adiponectin, and if the adiponectin receptor agonist AdipoRon improves IR and obesity in a PCOS model. Four-week-old female Sprague Dawley rats were implanted with dihydrotestosterone (DHT) or control Silastic tubes for 12 weeks. After 6 weeks of DHT treatment, rats received AdipoRon or vehicle in their food for 6 weeks. DHT increased body weight, fat and lean mass, food intake, serum leptin, adipose mitochondrial oxidative stress, inflammatory markers, HOMA-IR, adipocyte size, and decreased serum adiponectin levels. DHT upregulated GLUT4, PPARγ, and adiponectin mRNA expression in subcutaneous adipose tissue (SAT), while PPARγ was downregulated in visceral adipose tissue (VAT). DHT also reduced Akt protein expression in SAT and p(S473)-Akt phosphorylation in VAT and caused a depot-specific effect on androgen receptor expression. AdipoRon reduced body weight, fat, and lean mass, food intake, serum leptin, adipocyte size, and IR markers in DHT-treated rats. AdipoRon upregulated Akt, AMPK, and AdipoR1 mRNA expression in SAT and increased p(S473)-Akt phosphorylation in both white adipose tissue (WAT) depots. AdipoRon also reduced mitochondrial oxidative stress in both WAT depots and decreased androgen receptor expression in VAT. AdipoRon attenuates hyperandrogenemia-induced adiposity and IR in a PCOS model by improving adipose insulin and adiponectin signaling, reducing mitochondrial oxidative stress and food intake, supporting its therapeutic potential in managing IR and obesity in PCOS women.

IL-1R1 inhibition in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia lowered maternal blood pressure, reduced fetal reabsorptions, and improved fetal and placental growth. These effects were accompanied by restored systemic and placental immune balance but no improvement in vascular markers such as VEGF or preproendothelin. Thus, IL-1R1 blockade, including the clinical agent anakinra, is a promising therapeutic avenue that may require combination strategies for optimal benefit.

Previous studies have demonstrated that mammalian target of rapamycin (mTOR) activity is significantly increased in the kidneys of Dahl salt‐sensitive (SS) rats during the development of renal injury. Therefore, in the present study we examined whether blockade of mTOR with rapamycin inhibits renal injury in Dahl salt‐sensitive leptin receptor mutant (SS ^LepR mutant) rats. Four‐week‐old SS and SS ^LepR mutant rats were treated with either vehicle (saline, i.p. ) or rapamycin (1.5 mg/kg/day, i.p. ) for 4 weeks. Body weight was significantly higher in SS ^LepR mutant rats than in SS rats, and chronic treatment with rapamycin significantly decreased body weight only in SS ^LepR mutant rats. In vehicle‐treated rats, blood glucose levels were within the physiological range (≤120 mg/dL), and rapamycin treatment induced hyperglycaemia in SS ^LepR mutant rats (550 ± 54 mg/dL). Additionally, plasma insulin was significantly increased in SS ^LepR mutant rats versus SS rats, and rapamycin reduced plasma insulin in SS ^LepR mutant rats. Proteinuria was significantly higher in SS ^LepR mutant rats versus SS rats (564 ± 104 and 26 ± 12 mg/day, respectively), and rapamycin significantly decreased proteinuria in SS ^LepR mutant rats (48 ± 18 mg/day). Moreover, SS ^LepR mutant rats displayed renal hyperfiltration and marked glomerular and tubular injury compared with SS rats, and rapamycin improved these renal abnormalities in SS ^LepR mutant rats. Interestingly, we observed that renal sodium glucose cotransporter 2 (SGLT2) expression was significantly elevated in SS ^LepR mutant rats versus SS rats, and rapamycin markedly reduced renal SGLT2 expression in SS ^LepR mutant rats. Overall, these data indicate that mTOR plays an important role in renal metabolic disease in obese SS ^LepR mutant rats before puberty and suggest that rapamycin might prevent renal hyperfiltration associated with obesity by decreasing renal SGLT2 activity.

Hypertensive disorders of pregnancy (HDPs) are a leading cause of maternal and perinatal morbidity and mortality globally, affecting up to 10% of pregnancies. As rates of obesity, chronic hypertension, and advanced maternal age continue to rise, the burden of HDPs is expected to escalate. This review provides a comprehensive overview of HDPs, encompassing updated classification systems, risk factors, and diagnostic approaches, including emerging biomarkers and predictive imaging tools. We highlight the complex pathophysiology involving impaired placentation, angiogenic imbalance, immune dysregulation, oxidative stress, mitochondrial dysfunction, and epigenetic modifications. Current management strategies are discussed alongside evolving therapeutic interventions, including low-dose aspirin, statins, and novel agents such as hydrogen sulfide donors and C-type natriuretic peptide. Special emphasis is placed on racial, ethnic, and socioeconomic disparities that contribute to disproportionate outcomes, particularly among Black and Indigenous women. We also explore the role of personalized medicine, predictive models, and digital health tools in transforming HDP care. By integrating mechanistic insight with public health strategies and clinical innovation, this review aims to inform multidisciplinary approaches to reduce the burden of HDPs and promote equitable maternal and neonatal outcomes.

BACKGROUND: Patients with preeclampsia exhibit hypertension and chronic inflammation characterized by CD (cluster determinant) 4+T cells, B cells secreting AT1-AA (agonistic autoantibody against the angiotensin II type 1 receptor), inflammatory cytokines, and complement activation. Importantly, a history of COVID-19 during pregnancy is associated with an increased incidence of a preeclampsia-like phenotype and is partly mediated by CD4+T cells. We recently showed pregnant patients with a history of COVID-19 with or without preeclampsia produce AT1-AA, indicating the importance of B lymphocytes in the progression of preeclampsia and possibly of COVID-19. Therefore, we hypothesize that B cells from patients with preeclampsia with or without COVID-19 history induce the preeclampsia phenotype through AT1-AA. METHODS: Placental B cells were isolated from normal pregnant, patients with preeclampsia, normotensive COVID-19 history, or preeclampsia COVID-19 history at delivery. Then, 3×10 ⁵ B cells were transferred intraperitoneally into pregnant athymic rats at gestational day 12. On gestational day 18, carotid catheters were inserted. On gestational day 19, mean arterial pressure was measured, and tissues were collected. RESULTS: Preeclampsia B-cell recipients had significantly increased mean arterial pressure, AT1-AA, inflammatory cytokines, and complement activation compared with normal pregnant B-cell recipients. Recipients of B cells with COVID-19 history had markers of inflammation and hypertension but not to the level of significance as recipients of preeclampsia B cells. Inhibition of AT1-AA attenuated the hypertension that occurred in response to preeclampsia or preeclampsia B cells with COVID-19 history. CONCLUSIONS: This study demonstrates the important role of B cells in contributing to hypertension and chronic inflammation during preeclampsia with or without COVID-19 history through secretion of AT1-AA.

Maternal morbidity and mortality are disproportionately higher in minority racial and ethnic women in the United States. During pregnancy, the body’s protective system, or the immune system, is activated to aid in the development and progression of a successful pregnancy. Inflammation is a part of this activation; however, excessive inflammation causes more harm than good in the body. Black women experience more inflammation than their white counterparts, due to multiple factors. This excess inflammation may contribute to the significant maternal health disparities observed in Black women and other racial and ethnic minorities. Poor maternal health impacts the life of the mother and their child in both the short and the long term. This chapter explores the role of excessive inflammation in chronic diseases and poor maternal health. Additionally, a description of current efforts and recommendations to improve overall maternal health to eliminate health disparities in maternal and fetal outcomes are also described.

Problem: Preeclampsia (PE) is a hypertensive pregnancy disorder that is a leading cause of maternal and fetal morbidity and mortality characterized by maternal vascular dysfunction, oxidative stress, chronic immune activation, and excessive inflammation. No cure exists beyond delivery of the fetal–placental unit and the mechanisms driving pathophysiology are not fully understood. However, aberrant immune responses have been extensively characterized in clinical studies and shown to mediate PE pathophysiology in animal studies. One pathway that may mediate aberrant immune responses in PE is deficiencies in the IL‐33 signaling pathway. In this study, we aim to investigate the impact of IL‐33 signaling inhibition on cNK, T_H17, and T_Reg populations, vascular function, and maternal blood pressure during pregnancy.Method of Study: In this study, IL‐33 signaling was inhibited using two different methods: intraperitoneal administration of recombinant ST2 (which acts as a decoy receptor for IL‐33) and administration of a specific IL‐33 neutralizing antibody. Maternal blood pressure, uterine artery resistance index, renal and placental oxidative stress, cNK, T_H17, and T_Reg populations, various cytokines, and pre‐proendothelin‐1 levels were measured.Results: IL‐33 signaling inhibition increased maternal blood pressure, uterine artery resistance, placental and renal oxidative stress. IL‐33 signaling inhibition also increased placental cNK and T_H17 and renal T_H17 cells while decreasing placental T_Reg populations. IL‐33 neutralization increased circulating cNK and T_H17s and decreased circulating T_Regs in addition to increasing pre‐proendothelin‐1 levels.Conclusions: Data presented in this study demonstrate a role for IL‐33 signaling in controlling vascular function and maternal blood pressure during pregnancy possibly by mediating innate and adaptive immune inflammatory responses, identifying the IL‐33 signaling pathway as a potential therapeutic target for managing preeclampsia.