Atherosclerosis and Inflammation: Insights from the Theory of General Pathological Processes.

Recent advances have greatly improved our understanding of the molecular mechanisms behind atherosclerosis pathogenesis. However, there is still a need to systematize this data from a general pathology perspective, particularly with regard to atherogenesis patterns in the context of both canonical and non-classical inflammation types. In this review, we analyze various typical phenomena and outcomes of cellular pro-inflammatory stress in atherosclerosis, as well as the role of endothelial dysfunction in local and systemic manifestations of low-grade inflammation. We also present the features of immune mechanisms in the development of productive inflammation in stable and unstable plaques, along with their similarities and differences compared to canonical inflammation. There are numerous factors that act as inducers of the inflammatory process in atherosclerosis, including vascular endothelium aging, metabolic dysfunctions, autoimmune, and in some cases, infectious damage factors. Life-critical complications of atherosclerosis, such as cardiogenic shock and severe strokes, are associated with the development of acute systemic hyperinflammation. Additionally, critical atherosclerotic ischemia of the lower extremities induces paracoagulation and the development of chronic systemic inflammation. Conversely, sepsis, other critical conditions, and severe systemic chronic diseases contribute to atherogenesis. In summary, atherosclerosis can be characterized as an independent form of inflammation, sharing similarities but also having fundamental differences from low-grade inflammation and various variants of canonical inflammation (classic vasculitis).

Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders.

Preeclampsia is a devastating medical complication of pregnancy that can lead to significant maternal and fetal morbidity and mortality. It is currently believed that there is abnormal placentation in as early as the first trimester in women destined to develop preeclampsia. Although the etiology of the abnormal placentation is being debated, numerous epidemiologic and experimental studies suggest that imbalances in circulating angiogenic factors released from the placenta are responsible for the maternal signs and symptoms of preeclampsia. In particular, circulating levels of soluble fms-like tyrosine kinase 1, an antiangiogenic factor, are markedly increased in women with preeclampsia, whereas free levels of its ligand, placental, growth factor are markedly diminished. Alterations in these angiogenic factors precede the onset of clinical signs of preeclampsia and correlate with disease severity. Recently, the availability of automated assays for the measurement of angiogenic biomarkers in the plasma, serum, and urine has helped investigators worldwide to demonstrate a key role for these factors in the clinical diagnosis and prediction of preeclampsia. Numerous studies have reported that circulating angiogenic biomarkers have a very high negative predictive value to rule out clinical disease among women with suspected preeclampsia. These blood-based biomarkers have provided a valuable tool to clinicians to accelerate the time to clinical diagnosis and minimize maternal adverse outcomes in women with preeclampsia. Angiogenic biomarkers have also been useful to elucidate the pathogenesis of related disorders of abnormal placentation such as intrauterine growth restriction, intrauterine fetal death, twin-to-twin transfusion syndrome, and fetal hydrops. In summary, the discovery and characterization of angiogenic proteins of placental origin have provided clinicians a noninvasive blood-based tool to monitor placental function and health and for early detection of disorders of placentation. Uncovering the mechanisms of altered angiogenic factors in preeclampsia and related disorders of placentation may provide insights into novel preventive and therapeutic options.

Glomerular Endothelial Cell-Derived miR-200c Impairs Glomerular Homeostasis by Targeting Podocyte VEGF-A.

Deciphering the pathophysiological mechanisms of primary podocytopathies that can lead to end-stage renal disease and increased mortality is an unmet need. Studying how microRNAs (miRs) interfere with various signaling pathways enables identification of pathomechanisms, novel biomarkers and potential therapeutic options. We investigated the expression of miR-200c in urine from patients with different renal diseases as a potential candidate involved in podocytopathies. The role of miR-200c for the glomerulus and its potential targets were studied in cultured human podocytes, human glomerular endothelial cells and in the zebrafish model. miR-200c was upregulated in urine from patients with minimal change disease, membranous glomerulonephritis and focal segmental glomerulosclerosis and also in transforming growth factor beta (TGF-ß) stressed glomerular endothelial cells, but not in podocytes. In zebrafish, miR-200c overexpression caused proteinuria, edema, podocyte foot process effacement and glomerular endotheliosis. Although zinc finger E-Box binding homeobox 1/2 (ZEB1/2), important in epithelial to mesenchymal transition (EMT), are prominent targets of miR-200c, their downregulation did not explain our zebrafish phenotype. We detected decreased vegfaa/bb in zebrafish overexpressing miR-200c and could further prove that miR-200c decreased VEGF-A expression and secretion in cultured human podocytes. We hypothesize that miR-200c is released from glomerular endothelial cells during cell stress and acts in a paracrine, autocrine, as well as context-dependent manner in the glomerulus. MiR-200c can cause glomerular damage most likely due to the reduction of podocyte VEGF-A. In contrast, miR-200c might also influence ZEB expression and therefore EMT, which might be important in other conditions. Therefore, we propose that miR-200c-mediated effects in the glomerulus are context-sensitive.

Specialties of hystomorphometrical changes in placenta of women with early and late preeclampsia.

OBJECTIVE: The aim: To find out typical pathomorphological differences in placenta of women with early and late preeclampsia. PATIENTS AND METHODS: Materials and methods: Investigation includes 40 placentas from deliveries in women with preeclampsia (main group) and 40 placentas from physiological delivery in somatically healthy women, who had no complications during pregnancy (control group). Placentas in the main group were devided into two sub-groups (20 in each) - with early and late preeclampsia. Specialties of the blood vessels in normal pregnancy were investigated, and their structural transformation with the developement of preeclampsia, according to the appearence of perinatal pathology. Morphometrical data of the blood stream was investigated with the help of eyepiece and program Image Tools 3,6. RESULTS: Results: Significant decrease of weight (p<0,05), square and volume of placenta was common to early preeclampsia, comparing to the same characteristics in late Preeclampsia (PE). Specific gravity of villi without vessels, hardened blood vessels, hardened villi and fibrinoid altered vessels was increased statistically significantly (p<0,05) in placenta of women with early PE, comparing to women with late PE. The number of effective blood vessels crossings was determined mostly in late PE, comparing to the early form (p<0,05). Found out significant defferences (p<0,05) in changes of hystovasoarchitecture of placenta in early preeclampsia, according to the number of immature villi and villi with no signs of compensatory angiomatosis. CONCLUSION: Conclusions: Increased number of hypoplasia of placenta, breach of effective placental blood stream and significant decrease of compensatory and adaptive changes in placenta are more common to early PE, comparing to late PE.

Vitamin B3 Nicotinamide: A Promising Candidate for Treating Preeclampsia and Improving Fetal Growth.

Up to 8% of pregnant women suffer from preeclampsia (PE), a deadly disease characterized by high blood pressure (BP), blood vessel damage, called endotheliosis (vascular endothelial swelling with narrowing of capillary lumen), and high levels of protein in the urine. PE is often associated with premature delivery, which is a risk factor of cardiovascular and metabolic diseases among the offspring. Accordingly, establishing drug treatments of PE is in immediate needs. Currently, many of anti-hypertensive drugs cause malformation of the fetuses and are contraindicated for pregnant women. Anti-hypertensive drugs that are allowed to be used for treating pregnant women could lower BP of the mothers and reduce the risk of maternal death due to cardiovascular diseases such as cerebral hemorrhage. However, these anti-hypertensives do not improve endotheliosis and proteinuria. In fact, they reduce blood supply to the placentae and fetuses, which could lead to fetal growth restriction (FGR) and fetal and neonatal death. Until now, the only treatment for preeclamptic women has been delivery of the baby and placenta. Using three mechanistically different mouse models of PE, we have found that vitamin B3 nicotinamide (Nam) is the first safe drug that alleviates PE, and that Nam also alleviates or prevents miscarriage, prolongs pregnancy period, and improves the growth of the fetuses in mice with PE. Importantly, Nam has been used for pregnant and nursing women who have difficulty in taking sufficient meal. Nam could help treat or prevent PE and FGR associated with PE, if the treatment works in humans.

Nicotinamide ameliorates a preeclampsia-like condition in mice with reduced uterine perfusion pressure.

Preeclampsia (PE) is pregnancy-induced hypertension with proteinuria that typically develops after 20 wk of gestation. Antihypertensives currently used for PE reduce blood pressure of PE mothers but do not prevent preterm delivery and do not alleviate fetal growth restriction (FGR) associated with PE. We have recently shown that the activation of the endothelin (ET) system exacerbates PE. However, ET receptor antagonists are teratogenic and not suitable for pregnant women. The vitamin B3 nicotinamide (Nam) inhibits vasoconstriction by ET and is generally considered safe and harmless to babies. Nam also alleviates oxidative stress, which exacerbates PE and FGR. The aim of the present study was to evaluate therapeutic effects of Nam on the PE-like phenotype using a reduced uterine perfusion pressure (RUPP) model in mice that we have recently developed. We bilaterally ligated uterine vessels of pregnant mice and administered Nam or water daily by gavage. Nam improved maternal hypertension, proteinuria, and glomerular endotheliosis in RUPP mice. Moreover, Nam prolonged pregnancies and improved survival and growth of the embryos in RUPP PE mice. In conclusion, Nam alleviates the PE-like phenotype and FGR in the murine RUPP model. Nam could help treat maternal hypertension and FGR in human PE.

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

During the first trimester of human pregnancy, the maternal systemic circulation undergoes remarkable vasodilation. The kidneys participate in this vasodilatory response resulting in marked increases in renal plasma flow (RPF) and glomerular filtration rate (GFR). Comparable circulatory adaptations are observed in conscious gravid rats. Administration of the corpus luteal hormone relaxin (RLN) to nonpregnant rats and humans elicits vasodilatory changes like those of pregnancy. Systemic and renal vasodilation are compromised in midterm pregnant rats by neutralization or elimination of circulating RLN and in women conceiving with donor eggs who lack a corpus luteum and circulating RLN. Although RLN exerts both rapid (minutes) and sustained (hours to days) vasodilatory actions through different molecular mechanisms, a final common pathway is endothelial nitric oxide. In preeclampsia (PE), maternal systemic and renal vasoconstriction leads to hypertension and modest reduction in GFR exceeding that of RPF. Elevated level of circulating soluble vascular endothelial growth factor receptor-1 arising from the placenta is implicated in the hypertension and disruption of glomerular fenestrae and barrier function, the former causing reduced Kf and the latter proteinuria. Additional pathogenic factors are discussed. Last, potential clinical ramifications include RLN replacement in women conceiving with donor eggs and its therapeutic use in PE. Another goal has been to apply knowledge gained from investigating circulatory adaptations in pregnancy toward identifying and developing novel therapeutic strategies for renal and cardiovascular disease in the nonpregnant population. So far, one candidate to emerge is RLN and its potential therapeutic use in heart failure.

Glomerular Endotheliosis in COVID-19-Associated Acute Kidney Injury.

Acute kidney injury (AKI) has been seen in patients hospitalized with a SARS-CoV-2 (COVID-19) infection,but the pathophysiology of glomerular injury is not yet fully understood. We present a case of COVID-19-related "glomerular endotheliosis" in which a 51-year-old female with a 13-year history of class IV lupus nephritis was admitted for COVID-19 pneumonia. Her lupus nephritis had been in complete renal remission for the past 10 years with a baseline serum creatinine level of 1.3 mg/dL and no proteinuria. Her serological workup, including complement levels, was unremarkable. Due to the worsening renal function and persistent proteinuria, she underwent a kidney biopsy that revealed diffuse glomerular endothelial cell swelling, also known as glomerular endotheliosis. Her clinical course unfortunately deteriorated and she succumbed to acute respiratory distress syndrome. As circulating anti-angiogenic factors may contribute to the pathogenesis of endothelial dysfunction leading to glomerular endotheliosis, we propose that a similar circulating antiangiogenic factor may have been triggered by COVID-19 and played a role in our patient's progressive renal failure.

Preeclampsia: A close look at renal dysfunction.

Preeclampsia (PE) is a unique pathophysiologic situation that physiologic interests of mother, fetus, and placenta diverge. PE is related to the increased circulating antiangiogenic factors originated from hypoxic placenta. It is simply defined by the new onset of hypertension (≥140/90 mmHg) and proteinuria (≥0.3 g/day) after 20 weeks of gestation. PE is associated with kidney dysfunction due to deficiency in podocyte specific vascular endothelial growth factor (VEGF). Hypoxic placenta in PE patients produces increased levels of fms-like tyrosine kinase 1(sFlt-1), a soluble receptor of VEGF. sFlt-1 abrogates binding of VEGF to its receptor on endothelial cells and podocytes, and ultimately damages the filtration barrier. Glomerular endotheliosis and thrombotic microangiopathy (TMA) are the main features of kidney involvement in PE and can induce clotting and vessel occlusion. This complex pathophysiology is ameliorated after delivery; however, permanent kidney damages may remain and is intensified thereafter. This review aims to highlight the biochemical, genetic, and immunological-involved factors in the initiation of PE and explores the relationship between the kidney and PE. This work mainly discusses the pathologic mechanisms of kidney involvement in PE through the lens of the imbalanced VEGF-VEGF receptor signaling pathway.

Preeclampsia before 20 weeks of gestation: a case report and review of the literature.

The occurrence of preeclampsia before 20 weeks of gestation is rare and usually associated with trophoblastic diseases or antiphospholipid syndrome. Here, we report a case of preeclampsia before 20 weeks of gestation in the absence of the aforementioned disorders. A healthy 30-year-old nulliparous woman presented with new onset of hypertension and proteinuria at 18 weeks of gestation. Fetal ultrasound did not reveal any abnormalities. Empirical steroid treatment was initiated based on a tentative diagnosis of underlying renal disease. The clinical course of the disease was progressive despite steroid treatment and the fetus died in utero 8 days after the initiation of treatment. Following delivery, a renal biopsy was performed and provided a diagnosis of preeclampsia. All symptoms resolved postpartum. This report demonstrates that preeclampsia may occur before 20 weeks of gestation and should always be considered in the differential diagnosis of pregnant women with new onset of hypertension with proteinuria. Previous published cases are summarized briefly.