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Huoxue Jiedu Huayu recipe(活血解毒化瘀方) inhibits macrophage-secreted vascular endothelial growth factor-a on angiogenesis and alleviates renal fibrosis in the contralateral kidneys of unilateral ureteral obstruction rats

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Journal of Traditional Chinese Medicine 2024年第3期44卷 458-467页

作者： GAO Xiaomeng QIANG Panpan CHANG Jingyue FAN Lili YANG Fan XU Qingyou Graduate School Hebei University of Chinese Medicine Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns Hebei University of Chinese Medicine Institute of Integrative Medicine Hebei University of Chinese Medicine

OBJECTIVE: To elucidate the mechanism by which Huoxue Jiedu Huayu recipe( 活血解毒化瘀方, HJHR) regulates angiogenesis in the contralateral kidney of unilateral ureteral obstruction(UUO) rats and the mechanism by which it reduces of renal fibrosis. METHODS: Male Wistar rats were randomly divided into 4 groups: the sham group, UUO group(180 d of left ureter ligation), UUO plus eplerenone(EPL) group, and UUO plus HJHR group. After 180 d of oral drug administration, blood and contralateral kidneys were collected for analysis. Angiogenesis-and fibrosis-related indexes were detected. RESULTS: HJHR and EPL improved structural damage and renal interstitial fibrosis in the contralateral kidney and reduced the protein expression levels of α-smooth muscle actin(α-SMA), vimentin and collagen I. Moreover, these treatments could reduce the expression of vascular endothelial growth factor-A(VEGFA) by inhibiting the infiltration of macrophages. Furthermore, HJHR and EPL significantly reduced the expression of CD34 and CD105 by downregulating VEGFA production, which inhibited angiogenesis. Finally, the coexpressions of CD34, CD105 and α-SMA were decreased in the HJHR and EPL groups, indicating that endothelial-to-mesenchymal transition was inhibited. CONCLUSIONS: These findings confirm that HJHR alleviates contralateral renal fibrosis by inhibiting VEGFAinduced angiogenesis, encourage the use of HJHR against renal interstitial fibrosis and provide a theoretical basis for the clinical management of patients with CKD.

关键词： aldosterone epithelial-mesenchymal transition eplerenone Huoxue Jiedu Huayu recipe mineralocorticoid receptors unilateral ureteral obstruction

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An alternative splicing variant of mineralocorticoid receptor discovered in preeclampsia tissues and its effect on endothelial dysfunction

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Science China(Life Sciences) 2020年第3期63卷 388-400页

作者： Mengxi Guo Chengliang Zhou Gufeng Xu Lin Tang Yechun Ruan Ying Yu Xianhua Lin Dandan Wu Hao Chen Priscilla Yu Luyang Jin Yinyu Wang Yimei Wu Kamran Ullah Tanzil Ur Rahman Xinmei Liu Jianzhong Sheng Hsiao-Chang Chan Hefeng Huang Women’s Hospital Zhejiang University School of MedicineHangzhou 310058China International Peace Maternal and Child Health Hospital Shanghai Jiao Tong University School of MedicineShanghai 200030China Epithelial Cell Biology Research Center Faculty of MedicineSchool of Biomedical SciencesThe Chinese University of Hong KongHong KongChina Key Laboratory of Reproductive Genetics Ministry of Education(Zhejiang University)Hangzhou 310058China Department of Pathology and Pathophysiology Zhejiang University School of MedicineHangzhou 310058China Shanghai Key Laboratory of Embryo Original Disease Shanghai 20030China

The pathophysiology of preeclampsia(PE)remains unclear.PE spiral artery remodeling dysfunction and PE offspring cardiovascular future development has been a worldwide concern.We collected placental and umbilical artery samples from normotensive and PE pregnancies.mineralocorticoid receptor(MR)and its alternative splicing variant(ASV)expression and their biological effects on PE were examined.An MR ASV was found to be highly expressed in all PE samples and slightly expressed in about half of the normotensive samples(umbilical artery,~57.58%;placenta,~36.84%).The MR ASV expression was positively associated with blood pressure in both groups.The MR ASV protein changed the aldosterone-induced expression pattern of MR target genes related to ion exchanges and cell signaling pathways.The MR ASV can also impair the proliferation,migration,and tube formation ability of endothelial cells.These findings indicate that MR ASV in PE placenta plays a pathogenic role in PE pathophysiology,especially in endothelial dysfunction,and the existence of the MR ASV in PE umbilical artery provides a new direction in the study of PE offspring with increased risk of cardiovascular diseases.

关键词： preeclampsia mineralocorticoid receptor alternative splicing variant offspring endothelial dysfunction

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Effects of mineralocorticoid receptor antagonists on responses to hemorrhagic shock in rats

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World Journal of Critical Care Medicine 2018年第1期7卷 1-8页

作者： Kanako Yamamoto Takashi Yamamoto Masayuki Takamura Soichiro Usui Hisayoshi Murai Shuichi Kaneko Takumi Taniguchi Department of System Biology Kanazawa University Graduate School of Advanced Preventive Medical Sciences Kanazawa University Department of Anesthesiology and Intensive Care Medicine Kanazawa University Graduate School of Medical Sciences Kanazawa University

AIM To evaluate the effects of mineralocorticoid receptor(MR) antagonists on mortality and inflammatory responses after hemorrhagic shock(HS) in rats.METHODS One hundred and two male Sprague–Dawley rats were randomly assigned to one of the following three groups: Control, spironolactone (SPL), and eplerenone(EP) groups. HS was induced by the removal of blood. One half of rats were evaluated to determine mortality, hemodynamics, plasma tumor necrosis factor-alpha(TNF-α) concentrations, and arterial blood gas at 8 h afterHS recovery. In the remainder of rats, the expression levels of genes encoding cytokines were evaluated in liver tissue samples at 1 h after HS recovery. RESULTS The survival rates 8 h after HS recovery were 71%, 94%, and 82% in the control, SPL, and EP groups, respectively. There were no significant differences in survival rates among the three groups (P = 0.219). Furthermore, there were no significant differences in gene expression levels in the liver or plasma TNF-α concentrations among the three groups(P = 0.888).CONCLUSION Pretreatment with MR antagonists did not improve mortality or cytokine responses in the liver after HS recovery in rats.

关键词： Hemorrhagic shock Mortality Inflammatory response mineralocorticoid receptor antagonist Cytokine

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Achieving control of resistant hypertension:Not just the number of blood pressure medications

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World Journal of Hypertension 2019年第1期9卷 1-16页

作者： Kara Schmidt William Kelley Steven Tringali Jian Huang Department of Internal Medicine University of California San Francisco-Fresno Medical Education Program Medicine Service VA Central California Health Care System

Resistant hypertension(RH) has a prevalence of around 12% and is associated with an increased risk of cardiovascular disease, progression to end-stage renal disease, and even mortality. In 2017, the American College of Cardiology and American Heart Association released updated guidelines that detail steps to ensure proper diagnosis of RH, including the exclusion of pseudoresistance.Lifestyle modifications, such as low salt diet and physical exercise, remain at the forefront of optimizing blood pressure control. Secondary causes of RH also need to be investigated, including screening for obstructive sleep apnea. Notably, the guidelines demonstrate a major change in medication management recommendations to include mineralocorticoid receptor antagonists. In addition to advances in medication optimization, there are several device-based therapies that have been showing efficacy in the treatment of RH. Renal denervation therapy has struggled to show efficacy for blood pressure control, but with a redesigned catheter device, it is once again being tested in clinical trials. Carotid baroreceptor activation therapy(BAT) via an implantable pulse generator has been shown to be effective in lowering blood pressure both acutely and in longterm follow up data, but there is some concern about the safety profile. Both a second-generation pulse generator and an endovascular implant are being tested in new clinical trials with hopes for improved safety profiles while maintaining therapeutic efficacy. Both renal denervation and carotid BAT need continued study before widespread clinical implementation. Central arteriovenous anastomosis has emerged as another possible therapy and is being actively explored. The ongoing pursuit of blood pressure control is a vital part of minimizing adverse patient outcomes. The future landscape appears hopeful for helping patients achieve blood pressure goals not only through the optimization of antihypertensive medications but also through device-based therapies in select individuals.

关键词： Resistant hypertension Pseudoresistance mineralocorticoid receptor antagonists Device-based hypertension treatment Renal denervation Carotid baroreceptor activation therapy Central arteriovenous anastomosis

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Kidney in primary aldosteronism: A key determinant of treatment outcome

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World Journal of Hypertension 2012年第1期2卷 1-6页

作者： Cristiana Catena Gian Luca Colussi Leonardo A Sechi Hypertension Unit Internal Medicine Department of Experimental and Clinical Medicine Clinica Medica University of Udine University Hospital 33100 Udine Italy

Recently, it has been suggested that primary aldosteronism(PA) is associated with a variety of cardiac,vascular, metabolic, and renal sequelae that reflect the capability of elevated aldosterone to induce organ damage beyond that induced by hypertension itself. The evidence supporting of these views has been obtained from experiments conducted in rodents and clinica studies conducted in patients with this endocrine disorder. It has been suggested that untoward effects of high-salt intake are dependent on activation of mineralocorticoid receptors that might result from increased oxidative stress and changes in the intracellular redox potential. Unilateral adrenalectomy or treatment with mineralocorticoid receptor antagonists are the current options for treating an aldosterone-producing adrena adenoma or idiopathic adrenal hyperplasia. Treatments are largely effective in correcting hypertension and hypokalemia, and currently available information on their capability to prevent deterioration of renal function indicates that surgery and medical treatment are equallybeneficial in the long term. This editorial review will focus on the renal aspects of PA and highlights the role of the kidney as a key determinant of both adaptation to aldosterone-induced volume retention and response of blood pressure to treatment.

关键词： Blood pressure Glomerular filtration rate Albuminuria Adrenalectomy mineralocorticoid receptor antagonists

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Severe Ectopic Cushing’s Syndrome Due to ACTH-Secreting Pheochromocytoma

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International Journal of Clinical Medicine 2013年第4期4卷 228-231页

作者： Aurelio Negro Enrica Manicardi Chiara Grasselli Massimiliano Babini Rosaria Santi Valeria Pugni Lucia Spaggiari Elena Tagliavini Diabetologic Unit Arcispedale Santa Maria Nuova Reggio Emilia Italy Pathology Unit Arcispedale Santa Maria Nuova Reggio Emilia Italy Radiology Unit Arcispedale Santa Maria Nuova Reggio Emilia Italy Second Division of Internal Medicine and Hypertension Unit Arcispedale Santa Maria Nuova Reggio Emilia Italy

We report a new case of ectopic Cushing’s syndrome caused by an ACTH-producing pheochromocytoma. A 55-year-old woman presented with a history of severe proximal muscle weakness, polyuria, progressive virilization, anxiety, dyspnea on exercise, difficult to treat hypertension, and type 2 diabetes mellitus since 4 months. The laboratory data demonstrated ACTH-dependent hypercortisolism. The abdominal computed tomography scan showed a 30 mm well-defined mass in the left adrenal gland suggestive for pheochromocytoma. The adrenal veins were sampled, with intraprocedural cortisol measurement, to dosing selective ACTH and cathecolamines. The results established clearly the left adrenal gland as the source of ACTH overproduction. A left sided adrenalectomy was performed with subsequent resolution of Cushing’s syndrome. The patient was discharged in good clinical condition.

关键词： Cushing’s Syndrome Pheochromocytoma Apparent Excess of mineralocorticoid Syndrome

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Does MR play a vital role in the development of depressive disorder~

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中国药理学通报 2015年第B11期31卷 67-67页

作者： CHENJiao WANGZhen-zhen ZUOWei CHENNai-hong StateKeyLaboratoryofBioactiveSubstancesandFunctionsofNaturalMedicines InstituteofMateria&NeuroscienceCenterChineseAcademyofMedicalSciencesandPekingUnionMedicalCollegeBeijing

Depression is a leading cause of disability worldwide. However the biological and molecular mechanisms underlying this disorder remain to be unknown. Stress is a disposing factor in the development of depression, which could lead to HPA axis activation and the release of glucocorticoids. Glucocorticoids have two receptors, one is GR, the other is MR. Despite the fact that GR has been extensively studied, there is increasingly awareness that MR has a crucial role in the development of depression. This review summarizes how the MR plays a role in the pathophysiology of depression in HPA axis regulation, inflammation, neurogenesis as well as stress-related behav- iors. Considering that the research about MR in the development of depression is limited, further investigation of MR is needed for better understanding of this disease, which could contribute to the prevention and treatment of de- pressive disorder.

关键词： depression mineralocorticoid receptor glucocorticoid receptor stress

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