A case of juvenile-onset pheochromocytoma with KIF1B p.V1529M germline mutation.

In 2008, a familial noradrenergic pheochromocytoma (PCC) with a KIF1B germline mutation in exon 41 was reported in a 24-year-old female proband and her family. However, in 2020, the same research group reported that the cause of PCC in this family was a MAX germline mutation and was not due to the KIF1B mutation. In this study, we investigated the pathogenicity of a KIF1B germline mutation detected in a 26-year-old woman with juvenile-onset noradrenergic PCC. She was surgically treated and did not have a family history of PCC. We performed whole-exome sequencing, Sanger sequencing, and immunohistochemical and gene expression analyses of catecholamine-synthesizing enzymes. Three tumors with associated somatic mutations were used as the control group. Whole-exome sequencing revealed a p.V1529M KIF1B germline mutation in exon 41 in our patient, and no other associated germline and somatic mutations, including MAX, were detected. Sanger sequencing confirmed the presence of both mutant and wild-type alleles in the tumor. Among the catecholamine-synthesizing enzymes, the expression of phenylethanolamine-N-methyl transferase was suppressed. An in silico analysis of the p.V1529M mutation showed a score suggestive of pathogenicity. After evaluation with the international guideline for sequence variants, p.V1529M mutation was still classified as a variant with uncertain significance; however, our data, including the in silico analysis data, provided certain evidences that met the criteria supporting its pathogenicity. Therefore, this study can support future studies in proving the pathogenicity of the KIF1B p.V1529M mutation.

Nrf2 activation for kidney disease treatment-a mixed blessing?

Activation of cellular antioxidative signaling is expected to be a silver bullet against kidney diseases, and clinical trials of compounds activating the antioxidant transcription factor Nrf2 have revealed their renoprotective effects. However, cardiac events have been observed in some cases with elevated urinary albumin excretion in these trials. Therefore, elucidating the negative effects of Nrf2 activation is essential. Rush and colleagues demonstrated that Nrf2 activation aggravates podocyte injury, a factor related to proteinuria and cardiac failure.

Roles of Nrf2 in Protecting the Kidney from Oxidative Damage.

Over 10% of the global population suffers from kidney disease. However, only kidney replacement therapies, which burden medical expenses, are currently effective in treating kidney disease. Therefore, elucidating the complicated molecular pathology of kidney disease is an urgent priority for developing innovative therapeutics for kidney disease. Recent studies demonstrated that intertwined renal vasculature often causes ischemia-reperfusion injury (IRI), which generates oxidative stress, and that the accumulation of oxidative stress is a common pathway underlying various types of kidney disease. We reported that activating the antioxidative transcription factor Nrf2 in renal tubules in mice with renal IRI effectively mitigates tubular damage and interstitial fibrosis by inducing the expression of genes related to cytoprotection against oxidative stress. Additionally, since the kidney performs multiple functions beyond blood purification, renoprotection by Nrf2 activation is anticipated to lead to various benefits. Indeed, our experiments indicated the possibility that Nrf2 activation mitigates anemia, which is caused by impaired production of the erythroid growth factor erythropoietin from injured kidneys, and moderates organ damage worsened by anemic hypoxia. Clinical trials investigating Nrf2-activating compounds in kidney disease patients are ongoing, and beneficial effects are being obtained. Thus, Nrf2 activators are expected to emerge as first-in-class innovative medicine for kidney disease treatment.

Laparoscopic Sleeve Gastrectomy on Severe Obesity after Intracranial Germinoma Treatment: A Case Report.

Hypothalamic obesity is a clinical syndrome characterized by severe and refractory obesity that is caused by hypothalamic function impairment. Recently, bariatric surgery has been attempted for patients with hypothalamic obesity after craniopharyngioma, but experiences have not yet been accumulated in other hypothalamic disorders. Here, we report the case of a 39-year-old male patient with panhypopituitarism who received laparoscopic sleeve gastrectomy (LSG) after intracranial germinoma treatment. The patient was diagnosed with intracranial germinoma at age 15 and achieved complete remission after radiotherapy (total 50 Gy). He was obese during diagnosis [body mass index (BMI), 29.2 kg/m2], and his obesity gradually worsened after the intracranial germinoma treatment, and LSG was considered when his BMI was 48.6 kg/m2. After 1 month of hospitalized diet-exercise program, LSG was performed. After LSG, his BMI gradually decreased and reached 38.8 kg/m2 on the day of discharge (6 weeks after the surgery). Five months after LSG, his insulin resistance improved, but insulin hypersecretion remained. Fifteen months after the surgery, his BMI was 31.2 kg/m2, with marked decrease in visceral and subcutaneous fat areas (from 393.8 cm2 and 168.2 cm2 before the surgery to 111.5 cm2 and 56.3 cm2, respectively.). To our knowledge, this is the first case of LSG for hypothalamic obesity after intracranial germinoma treatment. Although the pathophysiology of hypothalamic obesity is different from that of primary obesity, LSG could be a successful therapeutic choice for patients with hypothalamic obesity after the intracranial germinoma treatment.

Effects of surgical treatment for acromegaly on knee MRI structural features.

Acromegalic arthropathy is a common complication of acromegaly and harms the quality of life of the patients even after acromegaly is in long-term remission. A recent study demonstrated by knee MRI the characteristic structural features of acromegalic arthropathy. However, the effects of treatment for acromegaly on such structural features are almost unknown. This study was undertaken to analyze the effects of transsphenoidal surgery (TSS) on acromegalic arthropathy and elucidate whether knee MRI findings are reversible or irreversible. We analyzed 22 patients with acromegaly (63.7% females, median age 58 years) by knee MRI at diagnosis. Out of these 22 patients, 16 who underwent TSS (68.9% female, median age 58 years) were also subjected to knee MRI 2 months after TSS. As for X-ray undetectable findings, MRI detected synovial thickening, bone marrow lesion, ligament injury and meniscus injury in 22.7%, 22.7%, 4.7% and 59.1% of the patients, respectively. With respect to the 16 patients who underwent TSS, clinical and structural improvements were observed respectively in 100%, 66.7% and 66.7% of the patients who showed knee joint pain, synovial thickening and bone marrow lesion before TSS. However, no patient showed structural improvement of meniscus injury after TSS. In acromegalic arthropathy, synovial thickening and bone marrow lesions are reversible while meniscus injury is irreversible. Because all those findings are associated with the exacerbation of arthropathy, they may be therapeutic targets for preventing the progression of arthropathy by endocrinological and orthopedic intervention.

Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression.

Acute kidney injury is a devastating disease with high morbidity in hospitalized patients and contributes to the pathogenesis of chronic kidney disease. An underlying mechanism of acute kidney injury involves ischemia-reperfusion injury which, in turn, induces oxidative stress and provokes organ damage. Nrf2 is a master transcription factor that regulates the cellular response to oxidative stress. Here, we examined the role of Nrf2 in the progression of ischemia-reperfusion injury-induced kidney damage in mice using genetic and pharmacological approaches. Both global and tubular-specific Nrf2 activation enhanced gene expression of antioxidant and NADPH synthesis enzymes, including glucose-6-phosphate dehydrogenase, and ameliorated both the initiation of injury in the outer medulla and the progression of tubular damage in the cortex. Myeloid-specific Nrf2 activation was ineffective. Short-term administration of the Nrf2 inducer CDDO during the initial phase of injury ameliorated the late phase of tubular damage. This inducer effectively protected the human proximal tubular cell line HK-2 from oxidative stress-mediated cell death while glucose-6-phosphate dehydrogenase knockdown increased intracellular reactive oxygen species. These findings demonstrate that tubular hyperactivation of Nrf2 in the initial phase of injury prevents the progression of reactive oxygen species-mediated tubular damage by inducing antioxidant enzymes and NADPH synthesis. Thus, Nrf2 may be a promising therapeutic target for preventing acute kidney injury to chronic kidney disease transition.

Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression.

BACKGROUND: Nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor for the antioxidative stress response and it activates a variety of cytoprotective genes related to redox and detoxification. NRF2 activity is regulated by the oxidative-stress sensor molecule Kelch-like ECH-associated protein 1 (KEAP1) that induces proteasomal degradation of NRF2 through ubiquitinating NRF2 under unstressed conditions. Because oxidative stress is a major pathogenic and aggravating factor for kidney diseases, the KEAP1-NRF2 system has been proposed to be a therapeutic target for renal protection. SUMMARY: Oxidative-stress molecules, such as reactive oxygen species, accumulate in the kidneys of animal models for acute kidney injury (AKI), in which NRF2 is transiently and slightly activated. Genetic or pharmacological enhancement of NRF2 activity in the renal tubules significantly ameliorates damage related to AKI and prevents AKI progression to chronic kidney disease (CKD) by reducing oxidative stress. These beneficial effects of NRF2 activation highlight the KEAP1-NRF2 system as an important target for kidney disease treatment. However, a phase-3 clinical trial of a KEAP1 inhibitor for patients with stage 4 CKD and type-2 diabetes mellitus (T2DM) was terminated due to the occurrence of cardiovascular events. Because recent basic studies have accumulated positive effects of KEAP1 inhibitors in moderate stages of CKD, phase-2 trials have been restarted. The data from the ongoing projects demonstrate that a KEAP1 inhibitor improves the glomerular filtration rate in patients with stage 3 CKD and T2DM without safety concerns. Key Message: The KEAP1-NRF2 system is one of the most promising therapeutic targets for kidney disease, and KEAP1 inhibitors could be part of critical therapies for kidney disease.

Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling.

Erythropoietin (Epo) is produced by renal Epo-producing cells (REPs) in a hypoxia-inducible manner. The conversion of REPs into myofibroblasts and coincident loss of Epo-producing ability are the major cause of renal fibrosis and anemia. However, the hypoxic response of these transformed myofibroblasts remains unclear. Here, we used complementary in vivo transgenic and live imaging approaches to better understand the importance of hypoxia signaling in Epo production. Live imaging of REPs in transgenic mice expressing green fluorescent protein from a modified Epo-gene locus revealed that healthy REPs tightly associated with endothelium by wrapping processes around capillaries. However, this association was hampered in states of renal injury-induced inflammation previously shown to correlate with the transition to myofibroblast-transformed renal Epo-producing cells (MF-REPs). Furthermore, activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) selectively in Epo-producing cells reactivated Epo production in MF-REPs. Loss of PHD2 in REPs restored Epo-gene expression in injured kidneys but caused polycythemia. Notably, combined deletions of PHD1 and PHD3 prevented loss of Epo expression without provoking polycythemia. Mice with PHD-deficient REPs also showed resistance to LPS-induced Epo repression in kidneys, suggesting that augmented HIF signaling counterbalances inflammatory stimuli in regulation of Epo production. Thus, augmentation of HIF signaling may be an attractive therapeutic strategy for treating renal anemia by reactivating Epo synthesis in MF-REPs.

Intra-adrenal Aldosterone Secretion: Segmental Adrenal Venous Sampling for Localization.

PURPOSE: To use segmental adrenal venous sampling (AVS) (S-AVS) of effluent tributaries (a version of AVS that, in addition to helping identify aldosterone hypersecretion, also enables the evaluation of intra-adrenal hormone distribution) to detect and localize intra-adrenal aldosterone secretion. MATERIALS AND METHODS: The institutional review board approved this study, and all patients provided informed consent. S-AVS was performed in 65 patients with primary aldosteronism (34 men; mean age, 50.9 years ± 11 [standard deviation]). A microcatheter was inserted in first-degree tributary veins. Unilateral aldosterone hypersecretion at the adrenal central vein was determined according to the lateralization index after cosyntropin stimulation. Excess aldosterone secretion at the adrenal tributary vein was considered to be present when the aldosterone/cortisol ratio from this vein exceeded that from the external iliac vein; suppressed secretion was indicated by the opposite pattern. Categoric variables were expressed as numbers and percentages; continuous variables were expressed as means ± standard errors of the mean. RESULTS: The AVS success rate, indicated by a selectivity index of 5 or greater, was 98% (64 of 65). The mean numbers of sampled tributaries on the left and right sides were 2.11 and 1.02, respectively. The following diagnoses were made on the basis of S-AVS results: unilateral aldosterone hypersecretion in 30 patients, bilateral hypersecretion without suppressed segments in 22 patients, and bilateral hypersecretion with at least one suppressed segment in 12 patients. None of the patients experienced severe complications. CONCLUSION: S-AVS could be used to identify heterogeneous intra-adrenal aldosterone secretion. Patients who have bilateral aldosterone-producing adenomas can be treated with adrenal-sparing surgery or other minimally invasive local therapies if any suppressed segment is identified at S-AVS.

[Renal erythropoietin-producing cells and kidney disease].

Erythropoietin(EPO) is an indispensable erythropoietic hormone, produced mainly from kidneys in adult, and the production declines with progression of chronic kidney disease(CKD). Renal EPO-producing cells(REPs) are peri-tubular interstitial fibroblasts. Dysfunction and myofibroblast transformation of REPs have been reported in rodent models of kidney injuries. Despite the crucial importance of EPO in health and diseases, many aspects of REPs remain to be elucidated because of technical difficulties to investi- gate the cells in vivo. This review will summarize our recent progress in characterization of REPs. We also summarize the role REPs play in kidney fibrosis and their unique character "plasticity". Future therapeutic approach targeting REPs to treat both anemia and fibrosis in CKD will also be discussed.

Update on Current Evidence for the Diagnosis and Management of Nonfunctioning Pituitary Neuroendocrine Tumors.

Pituitary neuroendocrine tumors (PitNETs) are the third most frequently diagnosed intracranial tumors, with nonfunctioning PitNETs (nfPitNETs) accounting for 30% of all pituitary tumors and representing the most common type of macroPitNETs. NfPitNETs are usually benign tumors with no evidence of hormone oversecretion except for hyperprolactinemia secondary to pituitary stalk compression. Due to this, they do not typically present with clinical syndromes like acromegaly, Cushing's disease or hyperthyroidism and instead are identified incidentally on imaging or from symptoms of mass effects (headache, vision changes, apoplexy). With the lack of effective medical interventions, first-line treatment is transsphenoidal surgical resection, however, nfPitNETs often have supra- or parasellar extension, and total resection of the tumor is often not possible, resulting in residual tumor regrowth or reoccurrence. While functional PitNETs can be easily followed for recurrence using hormonal biomarkers, there is no similar parameter to predict recurrence in nfPitNETs, hence delaying early recognition and timely management. Therefore, there is a need to identify prognostic biomarkers that can be used for patient surveillance and as therapeutic targets. This review focuses on summarizing the current evidence on nfPitNETs, with a special focus on potential new biomarkers and therapeutics.

Paraganglioma with High Levels of Dopamine, Dopa Decarboxylase Suppression, Dopamine ß-hydroxylase Upregulation and Intra-tumoral Melanin Accumulation: A Case Report with a Literature Review.

Object Exclusively dopamine-producing pheochromocytoma/paraganglioma (PPGL) is an extremely rare subtype. In this condition, intratumoral dopamine ß-hydroxylase (DBH), which controls the conversion of norepinephrine from dopamine, is impaired, resulting in suppressed norepinephrine and epinephrine production. However, the rarity of this type of PPGL hampers the understanding of its pathophysiology. We therefore conducted genetic and immunohistological analyses of a patient with an exclusively dopamine-producing paraganglioma. Methods Paraganglioma samples from a 52-year-old woman who presented with a 29.6- and 41.5-fold increase in plasma and 24-h urinary dopamine, respectively, but only a minor elevation in the plasma norepinephrine level was subjected to immunohistological and gene expression analyses of catecholamine synthases. Three tumors carrying known somatic PPGL-related gene variants (HRAS, EPAS1) were used as controls. Whole-exome sequencing (WES) was also performed using the patient's blood and tumor tissue. Results Surprisingly, the protein expression of DBH was not suppressed, and its mRNA expression was clearly higher in the patient than in the controls. Furthermore, dopa decarboxylase (DDC), which governs the conversion of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) to dopamine, was downregulated at the protein and gene levels. In addition, melanin, which is synthesized by L-DOPA, accumulated in the tumor. WES revealed no PPGL-associated pathogenic germline variants, but a missense somatic variant (c.1798G>T) in CSDE1 was identified. Conclusion Although pre-operative plasma L-DOPA was not measured, our histological and gene expression analyses suggest that L-DOPA, rather than dopamine, might have been overproduced in the tumor. This raises the possibility of pathophysiological heterogeneity in exclusively dopamine-producing PPGL.

Renal interstitial fibroblasts coproduce erythropoietin and renin under anaemic conditions.

BACKGROUND: Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown. METHODS AND FINDINGS: We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure. INTERPRETATION: Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin. FUNDING: Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation.

Pheochromocytoma Diagnosed during the Treatment of Diffuse Alveolar Hemorrhage, a Diagnostic Necessity before Using High-dose Glucocorticoids.

A 46-year-old woman with exacerbating hemoptysis and dyspnea was diagnosed with diffuse alveolar hemorrhage (DAH). High doses of glucocorticoids were initiated, but afterward, paroxysmal hypertension (210/140 mmHg) with headache and abdominal pain appeared. A 50-mm left adrenal tumor with an intense uptake by iodine-123 metaiodobenzylguanidine scintigraphy and catecholamine hypersecretion revealed complication with pheochromocytoma. Because high doses of glucocorticoids, sometimes required for DAH, can provoke life-threatening paroxysmal hypertension in pheochromocytoma and paraganglioma (PPGL), our case suggests that PPGL needs to be recognized as the cause of DAH and should be detected with whole-body imaging before starting glucocorticoids.

[Case of Neuro-Behçet disease resembling bacterial meningitis].

A 30-year-old man with intractable headache and high fever came to the emergency room. He presented skin eruption, aphtha, drowsiness (E3, V4, M6/GCS), meningeal sign, hyperreflexia, and bilateral papilloedema. He also showed pleocytosis (1,066/microl, polymorphonuclear cells predominantly) and pressure increase in CSF. WBC count and CRP were elevated. Two years before, he had meningeal sign, cervical myelitis, skin eruption, uveitis, and aphtha, and was diagnosed as Neuro-BehCet (NBD) disease. HLA-B52 and B55 were positive. We suspected recurrent NBD, but we couldn't exclude bacterial meningitis because of his symptoms and cell-pattern in CSF. We treated him with intravenous methylpredonisolone and antibiotics (MEPM 6 g/day and VCM 2 g/day). His symptoms dramatically improved within a few days. The rapid improvement might be attributed to the steroids. Furthermore, MRI FLAIR images showed multiple small high lesions in the brainstem, hemispheres, subcortical area, putamen and left cerebellar hemisphere. Serum procalcitonin was not increased. We diagnosed the recurrence of NBD retrospectively. Procalcitonin may be a useful marker for discrimination between meningitis due to NBD and septic meningitis.

Image quality and radiation dose of low-tube-voltage CT with reduced contrast media for right adrenal vein imaging.

OBJECTIVES: To compare image quality and radiation dose of right adrenal vein (RAV) imaging computed tomography (CT) among conventional, low kV, and low kV with reduced contrast medium protocols. METHODS: One-hundred-and-twenty patients undergoing adrenal CT were randomly assigned to one of three protocols: contrast dose of 600mgI/kg at 120-kV tube voltage setting (600-120 group), 600mgI/kg at 80kV (600-80 group), and 360mgI/kg at 80kV (360-80 group). Iterative reconstruction was used for 80-kV groups. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the RAV and size-specific dose estimates (SSDE) were measured. Three radiologists evaluated 4-point visualisation scores of RAV by consensus reading. RESULTS: The RAV detectability was 95%, 97.2%, and 97.3% for 600-120, 600-80, and 360-80 groups, respectively (p=1.000). Visualisation scores were not significantly different among the groups (p=0.152). There were no significant differences in CNR or SNR between the 600-120 and 360-80 groups. SSDE of the 360-80 group was significantly lower than that of the 600-120 group (5.86mGy±1.44 vs. 7.27mGy±1.81, p<0.001). CONCLUSIONS: 80-kV scans with 360 mgI/kg contrast media showed comparable detectability of RAV to conventional scans, while reducing 19% of SSDE.

Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury.

Acute kidney injury (AKI) is a leading cause of chronic kidney disease. Proximal tubules are considered to be the primary origin of pathogenic inflammatory cytokines in AKI. However, it remains unclear whether other cell types, including collecting duct (CD) cells, participate in inflammatory processes. The transcription factor GATA2 is specifically expressed in CD cells and maintains their cellular identity. To explore the pathophysiological function of GATA2 in AKI, we generated renal tubular cell-specific Gata2 deletion (G2CKO) mice and examined their susceptibility to ischemia reperfusion injury (IRI). Notably, G2CKO mice exhibited less severe kidney damage, with reduced granulomacrophagic infiltration upon IRI. Transcriptome analysis revealed that a series of inflammatory cytokine genes were downregulated in GATA2-deficient CD cells, suggesting that GATA2 induces inflammatory cytokine expression in diseased kidney CD cells. Through high-throughput chemical library screening, we identified a potent GATA inhibitor. The chemical reduces cytokine production in CD cells and protects the mouse kidney from IRI. These results revealed a novel pathological mechanism of renal IRI, namely, that CD cells produce inflammatory cytokines and promote IRI progression. In injured kidney CD cells, GATA2 exerts a proinflammatory function by upregulating inflammatory cytokine gene expression. GATA2 can therefore be considered a therapeutic target for AKI.

Derepression of the DNA Methylation Machinery of the Gata1 Gene Triggers the Differentiation Cue for Erythropoiesis.

GATA1 is a critical regulator of erythropoiesis. While the mechanisms underlying the high-level expression of GATA1 in maturing erythroid cells have been studied extensively, the initial activation of the Gata1 gene in early hematopoietic progenitors remains to be elucidated. We previously identified a hematopoietic stem and progenitor cell (HSPC)-specific silencer element (the Gata1 methylation-determining region [G1MDR]) that recruits DNA methyltransferase 1 (Dnmt1) and provokes methylation of the Gata1 gene enhancer. In the present study, we hypothesized that removal of the G1MDR-mediated silencing machinery is the molecular basis of the initial activation of the Gata1 gene and erythropoiesis. To address this hypothesis, we generated transgenic mouse lines harboring a Gata1 bacterial artificial chromosome in which the G1MDR was deleted. The mice exhibited abundant GATA1 expression in HSPCs, in a GATA2-dependent manner. The ectopic GATA1 expression repressed Gata2 transcription and induced erythropoiesis and apoptosis of HSPCs. Furthermore, genetic deletion of Dnmt1 in HSPCs activated Gata1 expression and depleted HSPCs, thus recapitulating the HSC phenotype associated with GATA1 gain of function. These results demonstrate that the G1MDR holds the key to HSPC maintenance and suggest that release from this suppressive mechanism is a fundamental requirement for subsequent initiation of erythroid differentiation.

Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes.

Placental activation of the renin-angiotensin system (RAS) plays a key role in the pathogenesis of preeclampsia. Reactive oxygen species (ROS) are thought to affect placental angiogenesis, which is critical for preventing preeclampsia pathology. We examined the role of ROS in preeclampsia by genetically modifying the Keap1-Nrf2 pathway, a cellular antioxidant defense system, in a mouse model of RAS-induced preeclampsia. Nrf2 deficiency would be expected to impair cellular antioxidant responses; however, Nrf2 deficiency in preeclamptic mice improved maternal and fetal survival, ameliorated intra-uterine growth retardation, and augmented oxidative DNA damage. Furthermore, the placentas of Nrf2-deficient mice had increased endothelial cell proliferation with dense vascular networks. In contrast, the placentas of preeclamptic mice with overactive Nrf2 showed repressed angiogenesis, which was associated with decreased expression of genes encoding angiogenic chemokines and cytokines. Our findings support the notion that ROS-mediated signaling is essential for maintaining placental angiogenesis in preeclampsia and may provide mechanistic insight into the negative results of clinical trials for antioxidants in preeclampsia.