The placenta is an essential organ that is formed during pregnancy and its proper development is critical for embryonic survival. While several animal models have been shown to exhibit some of the pathological effects present in human preeclampsia, these models often do not represent the physiological aspects that have been identified. Hypoxia-inducible factor 1 alpha (Hif-1α) is a necessary component of the cellular oxygen-sensing machinery and has been implicated as a major regulator of trophoblast differentiation. Elevated levels of Hif-1α in the human placenta have been linked to the development of pregnancy-associated disorders, such as preeclampsia and fetal growth restriction. As oxygen regulation is a critical determinant for placentogenesis, we determined the effects of constitutively active Hif-1α, specifically in trophoblasts, on mouse placental development in vivo . Our research indicates that prolonged expression of trophoblast-specific Hif-1α leads to a significant decrease in fetal birth weight. In addition, we noted significant physiological alterations in placental differentiation that included reduced branching morphogenesis, alterations in maternal and fetal blood spaces, and failure to remodel the maternal spiral arteries. These placental alterations resulted in subsequent maternal hypertension with parturitional resolution and maternal kidney glomeruloendotheliosis with accompanying proteinuria, classic hallmarks of preeclampsia. Our findings identify Hif-1α as a critical molecular mediator of placental development and indicate that prolonged expression of Hif-1α, explicitly in placental trophoblasts causes maternal pathology and establishes a mouse model that significantly recapitulates the physiological and pathophysiological characteristics of preeclampsia with fetal growth restriction.
Williams CR, Lu X, Sutliff RL, Hart CM. Rosiglitazone attenuates NF-B-mediated Nox4 upregulation in hyperglycemia-activated endothelial cells. Am J Physiol Cell Physiol 303: C213-C223, 2012. First published May 9, 2012; doi:10.1152/ajpcell.00227.2011.-Vascular complications, a major cause of morbidity and mortality in diabetic patients, are related to hyperglycemia-induced oxidative stress. Previously, we reported that rosiglitazone (RSG) attenuated vascular expression and activity of NADPH oxidases in diabetic mice. The mechanisms underlying these effects remain to be elucidated. We hypothesized that RSG acts directly on endothelial cells to modulate vascular responses in diabetes. To test this hypothesis, human aortic endothelial cells (HAECs) were exposed to normal glucose (NG; 5.6 mmol/l) or high glucose (HG; 30 mmol/l) concentrations. Select HAEC monolayers were treated with RSG, caffeic acid phenethyl ester (CAPE), diphenyleneiodonium (DPI), small interfering (si)RNA (to NF-B/p65 or Nox4), or Tempol. HG increased the expression and activity of the NADPH oxidase catalytic subunit Nox4 but not Nox1 or Nox2. RSG attenuated HG-induced NF-B/p65 phosphorylation, nuclear translocation, and binding to the Nox4 promoter. Inhibiting NF-B with CAPE or siNF-B/p65 also reduced HG-induced Nox4 expression and activity. HG-induced H 2O2 production was attenuated by siRNA-mediated knockdown of Nox4, and HG-induced HAEC monocyte adhesion was attenuated by treatment with RSG, DPI, CAPE, or Tempol. These results indicate that HG exposure stimulates HAEC NF-B activation, Nox4 expression, and H 2O2 production and that RSG attenuates HG-induced oxidative stress and subsequent monocyte-endothelial interactions by attenuating NF-B/p65 activation and Nox4 expression. This study provides novel insights into mechanisms by which the thiazolidinedione peroxisome proliferatoractivated receptor-␥ ligand RSG favorably modulates endothelial responses in the diabetic vasculature.peroxisome proliferator-activated receptor-␥; nuclear factor-B; hyperglycemia; reduced nicotinamide adenine dinucleotide phosphatase oxidase; reactive oxygen species DIABETES MELLITUS IS CURRENTLY estimated to affect 285 million individuals worldwide (50). Cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients (2,24). This diabetic complication is partially caused by the detrimental effects of hyperglycemia (9), a critical mediator in the development and progression of atherosclerosis (3). Hyperglycemia-induced oxidative stress stimulates endothelial dysfunction, which is associated with endothelial activation and the upregulation of cellular adhesion molecules, cytokines, and chemokines (15,22,49). Collectively, these endothelial alterations promote monocyte binding to vascular endothelium and eventual monocyte migration into the subendothelial space, key initiating events in the development of atherosclerosis.The mitochondrial electron transport chain, xanthine oxidase, uncoupled endothelial nitric oxide synthase, and NADPH oxi...
Zn deficiency (ZnD) is comorbid with chronic kidney disease and worsens kidney complications. Oxidative stress is implicated in the detrimental effects of ZnD. However, the sources of oxidative stress continue to be identified. Since NADPH oxidases (Nox) are the primary enzymes that contribute to renal reactive oxygen species generation, this study's objective was to determine the role of these enzymes in ZnD-induced oxidative stress. We hypothesized that ZnD promotes NADPH oxidase upregulation, resulting in oxidative stress and kidney damage. To test this hypothesis, wild-type mice were pair-fed a ZnD or Zn-adequate diet. To further investigate the effects of Zn bioavailability on NADPH oxidase regulation, mouse tubular epithelial cells were exposed to the Zn chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) or vehicle followed by Zn supplementation. We found that ZnD diet-fed mice develop microalbuminuria, electrolyte imbalance, and whole kidney hypertrophy. These markers of kidney damage are accompanied by elevated Nox2 expression and HO levels. In mouse tubular epithelial cells, TPEN-induced ZnD stimulates HO generation. In this in vitro model of ZnD, enhanced HO generation is prevented by NADPH oxidase inhibition with diphenyleneiodonium. Specifically, TPEN promotes Nox2 expression and activation, which are reversed when intracellular Zn levels are restored following Zn supplementation. Finally, Nox2 knockdown by siRNA prevents TPEN-induced HO generation and cellular hypertrophy in vitro. Together, these findings reveal that Nox2 is a Zn-regulated enzyme that mediates ZnD-induced oxidative stress and kidney hypertrophy. Understanding the specific mechanisms by which ZnD contributes to kidney damage may have an important impact on the treatment of chronic kidney disease.
Organ transplantation is the state of the art for treating end-stage organ failure. Over 25 000 organ transplants are performed in the USA each year. Survival rates following transplantation are now approaching 90% for 1 year and 75% for 5 years. Central to this success was the introduction of drugs that suppress the immune system and prevent rejection. The most commonly used class of immunosuppressing drugs are calcineurin inhibitors (CNIs). Calcineurin is a ubiquitous enzyme that is important for T-cell function. With more people taking CNIs for longer and longer periods of time the consequences of calcineurin inhibition on other organ systems – particularly the kidney – have become a growing concern. Virtually all people who take a CNI will develop some degree of kidney toxicity and up to 10% will progress to kidney failure. In the past 15 years, research into calcineurin action has identified distinct actions of the two main isoforms of the catalytic subunit of the enzyme. The α-isoform is required for kidney function whereas the β-isoform has a predominant role in the immune system. This review will discuss the current state of knowledge about calcineurin isoforms and how these new insights may reshape post-transplant immunosuppression.
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