Xiangmin Zhao - Academia.edu (original) (raw)

Papers by Xiangmin Zhao

Journal of the American Society of Nephrology, 2018

BackgroundThe mammalian kidney develops through reciprocal inductive signals between the metaneph... more BackgroundThe mammalian kidney develops through reciprocal inductive signals between the metanephric mesenchyme and ureteric bud. Transcription factor 21 (Tcf21) is highly expressed in the metanephric mesenchyme, including Six2-expressing cap mesenchyme and Foxd1-expressing stromal mesenchyme.Tcf21knockout mice die in the perinatal period from severe renal hypodysplasia. In humans,Tcf21mRNA levels are reduced in renal tissue from human fetuses with renal dysplasia. The molecular mechanisms underlying these renal defects are not yet known.MethodsUsing a variety of techniques to assess kidney development and gene expression, we compared the phenotypes of wild-type mice, mice with germline deletion of theTcf21gene, mice with stromal mesenchyme–specificTcf21deletion, and mice with cap mesenchyme–specificTcf21deletion.ResultsGermline deletion ofTcf21leads to impaired ureteric bud branching and is accompanied by downregulated expression ofGdnf-Ret-Wnt11, a key pathway required for branchi...

American Journal of Physiology-Heart and Circulatory Physiology, 2016

Interleukin-8 (IL8) is highly expressed by injured arteries in a variety of diseases and is a che... more Interleukin-8 (IL8) is highly expressed by injured arteries in a variety of diseases and is a chemoattractant for neutrophils which express IL8 receptors IL8RA and RB (IL8RA/B) on their membranes. Neutrophils interact with the damaged endothelium and initiate an inflammatory cascade at the site of injury. We have generated a novel translational targeted cell therapy for acute vascular injury using adenoviral vectors to overexpress IL8RA/B and green fluorescent protein (GFP) on the surface of endothelial cells (ECs) derived from human induced pluripotent stem cells (HiPS-IL8RA/B-ECs). We hypothesize that HiPS-IL8RA/B-ECs transfused intravenously into rats with balloon injury of the carotid artery will target to the injured site and compete with neutrophils, thus inhibiting inflammation and neointima formation. Young adult male Sprague-Dawley rats underwent balloon injury of the right carotid artery and received intravenous transfusion of saline vehicle, 1.5 × 106 HiPS-ECs, 1.5 × 106 ...

Clinical & Experimental Metastasis, 2014

A significant percentage of breast cancer victims will suffer from metastases indicating that new... more A significant percentage of breast cancer victims will suffer from metastases indicating that new approaches to preventing breast cancer metastasis are thus needed. Dietary stearate and chemotherapy have been shown to reduce breast cancer metastasis. We tested the complementary use of dietary stearate with a taxol-based chemotherapy which work through separate mechanisms to reduce breast cancer metastasis. We therefore carried out a prevention study in which diets were initiated prior to human MDA-MB-435 cancer cells being injected into the host and a treatment study in which diets were combined with paclitaxel (PTX). Using an orthotopic athymic nude mouse model and three diets (corn oil control diet/CO, low fat /LF or stearate/ST) the prevention study demonstrated that the ST diet decreased the incidence of lung metastasis by 50% compared to both the LF and CO diets. The ST diet also reduced the number and size of metastatic lung nodules compared to the LF diet. Results of the treatment study indicated that both the CO and ST diets decreased the number of mice with lung metastasis compared to the LF diet. Both CO and ST also decreased the number of lung metastases per mouse compared to the LF diet however only the ST diet cohort was significant. Histomorphometric analysis of the lung tumor tissue indicated that the ST diet plus PTX decreased angiogenesis compared to the LF diet plus PTX. In conclusion these results support combining diet with chemotherapy in both treatment and prevention settings.

Regulatory Peptides, 2005

Free Radical Biology and Medicine, 2014

Journal of the American Society of Hypertension, 2014

further confirmed in vitro. ZS-9's exchange capacity for Ca 2+ and Mg 2+ was below a measurable l... more further confirmed in vitro. ZS-9's exchange capacity for Ca 2+ and Mg 2+ was below a measurable level of 0.05 mEq/g. At a 1:1:1 ratio mixture of K + to Ca 2+ to Mg 2+ , KEC was 0.3 mEq/g for SPS and 2.7 mEq/g for ZS-9. Hence, ZS-9 was at least 25 times more selective for K + than Ca 2+ or Mg 2+ while SPS's selectivity for K + was only 0.2 times over the divalent cations. Conclusion: In an environment with K + , Ca 2+ , and Mg 2+ , ZS-9 appeared to be highly selective for K + whereas SPS was more selective for Ca 2+ , confirming earlier reports from the literature. Additionally, ZS-9's capacity for K + was w9 times that of SPS. If approved, ZS-9 may represent a novel first-in-class therapy for hyperkalemia with improved selectivity and capacity for K + .

Cardiovascular Diabetology, 2008

Background Different mechanisms of diabetic-induced NO dysfunction have been proposed and central... more Background Different mechanisms of diabetic-induced NO dysfunction have been proposed and central to most of them are significant changes in eNOS function as the rate-limiting step in NO bioavailability. eNOS exists in both monomeric and dimeric conformations, with the dimeric form catalyzing the synthesis of nitric oxide, while the monomeric form catalyzes the synthesis of superoxide (O2 -). Diabetic-induced shifts to decrease the dimer:monomer ratio is thought to contribute to the degradation of nitric oxide (NO) bioavailability. Exercise has long been useful in the management of diabetes. Although exercise-induced increases expression of eNOS has been reported, it is unclear if exercise may alter the functional coupling of eNOS. Methods To investigate this question, Goto-Kakizaki rats (a model of type II diabetes) were randomly assigned to a 9-week running program (train) or sedentary (sed) groups. Results Exercise training significantly (p < .05) increased plantaris muscle cy...

American Journal of Physiology-Lung Cellular and Molecular Physiology, 2004

We previously reported that angiotensin II stimulates an increase in nitric oxide production in p... more We previously reported that angiotensin II stimulates an increase in nitric oxide production in pulmonary artery endothelial cells. The aims of this study were to determine which receptor subtype mediates the angiotensin II-dependent increase in nitric oxide production and to investigate the roles of the angiotensin type 1 and type 2 receptors in modulating angiotensin II-dependent vasoconstriction in pulmonary arteries. Pulmonary artery endothelial cells express both angiotensin II type 1 and type 2 receptors as assessed by RT-PCR, Western blot analysis, and flow cytometry. Treatment of the endothelial cells with PD-123319, a type 2 receptor antagonist, prevented the angiotensin II-dependent increase in nitric oxide synthase mRNA, protein levels, and nitric oxide production. In contrast, the type 1 receptor antagonist losartan enhanced nitric oxide synthase mRNA levels, protein expression, and nitric oxide production. Pretreatment of the endothelial cells with either PD-123319 or a...

American Journal of Physiology-Heart and Circulatory Physiology, 2009

Mitochondrial reactive oxygen species (ROS) are potentially important in vascular oxygen-sensing ... more Mitochondrial reactive oxygen species (ROS) are potentially important in vascular oxygen-sensing mechanisms because hypoxia appears to be a stimulus for mitochondrial ROS generation; however, scavenging of endogenous ROS does not alter relaxation of endothelium-denuded bovine coronary arteries (BCA) to hypoxia. The purpose of this study was to investigate the influence of increasing mitochondrial ROS on the relaxation of BCA to hypoxia. Increasing mitochondrial superoxide with inhibitors of electron transport (10 μM rotenone and antimycin) and by opening mitochondrial ATP-dependent K+ channels with 100 μM diazoxide were observed in this study to attenuate relaxation of BCA precontracted with 30 mM KCl to hypoxia by 68–76% and 38%, respectively. This effect of rotenone is not prevented by inhibiting NADPH oxidase (Nox) activation or scavenging superoxide with Peg-SOD; however, it is reversed 85% and 26% by increasing the consumption of intracellular peroxide by 0.1 mM ebselen and 32....

AJP: Heart and Circulatory Physiology, 2009

Endothelium-denuded bovine pulmonary arteries (BPA) contract to hypoxia through a mechanism poten... more Endothelium-denuded bovine pulmonary arteries (BPA) contract to hypoxia through a mechanism potentially involving removing a superoxide-derived hydrogen peroxide-mediated relaxation. BPA organ cultured for 24 h with 0.1 mM cobalt chloride (CoCl2) to increase the expression and activity of heme oxygenase-1 (HO-1) is accompanied by a decrease in 5 μM lucigenin-detectable superoxide and an increase in horseradish peroxidase-luminol detectable peroxide levels. Force development to KCl in BPA was not affected by increases in HO-1, but the hypoxic pulmonary vasoconstriction (HPV) response was decreased. Organ culture with a HO-1 inhibitor (10 μM chromium mesoporphyrin) reversed the effects of HO-1 on HPV and peroxide. Treatment of HO-1-induced BPA with extracellular catalase resulted in reversal of the attenuation of HPV without affecting the force development to KCl. Increasing intracellular peroxide scavenging with 0.1 mM ebselen increased force development to KCl and partially reversed...

American Journal of Physiology-Heart and Circulatory Physiology, 2010

Hypoxia appears to promote contraction [hypoxic pulmonary vasoconstriction (HPV)] of bovine pulmo... more Hypoxia appears to promote contraction [hypoxic pulmonary vasoconstriction (HPV)] of bovine pulmonary arteries (BPA) through removal of a peroxide-mediated relaxation. This study examines the roles of BPA Nox oxidases and mitochondria in the HPV response. Inhibitors of Nox2 (0.1 mM apocynin and 50 μM gp91-dstat) and mitochondrial electron transport (10 μM antimycin and rotenone) decreased superoxide generation in BPA without affecting contraction to 25 mM KCl or the HPV response. Transfection of BPA with small inhibitory RNA (siRNA) for Nox2 and Nox4 decreased Nox2 and Nox4 protein expression, respectively, associated with an attenuation of superoxide detection, without affecting 25 mM KCl contraction. However, Nox4 siRNA, but not Nox2, attenuated HPV in BPA. A Nox4 inhibitor plumbagin (10 μM) increased basal force, decreased superoxide detection and peroxide release, and caused BPA to relax under hypoxia. Although acute removal of peroxide with 0.1 mM ebselen increased 25 mM KCl co...

American Journal of Physiology-Heart and Circulatory Physiology, 2013

The endothelium is a dynamic component of the cardiovascular system that plays an important role ... more The endothelium is a dynamic component of the cardiovascular system that plays an important role in health and disease. This study tested the hypothesis that targeted delivery of endothelial cells (ECs) overexpressing neutrophil membrane IL-8 receptors IL8RA and IL8RB reduces acute myocardial infarction (MI)-induced left ventricular (LV) remodeling and dysfunction and increases neovascularization in the area at risk surrounding the infarcted tissue. MI was created by ligating the left anterior descending coronary artery in 12-wk-old male Sprague-Dawley rats. Four groups of rats were studied: group 1: sham-operated rats without MI or EC transfusion; group 2: MI rats with intravenous vehicle; group 3: MI rats with transfused ECs transduced with empty adenoviral vector (Null-EC); and group 4: MI rats with transfused ECs overexpressing IL8RA/RB (1.5 × 106 cells post-MI). Two weeks after MI, LV function was assessed by echocardiography; infarct size was assessed by triphenyltetrazolium c...

American Journal of Physiology-Cell Physiology, 2007

We have previously reported that angiotensin II (ANG II) stimulated Src tyrosine kinase via a per... more We have previously reported that angiotensin II (ANG II) stimulated Src tyrosine kinase via a pertussis toxin-sensitive type 2 receptor, which, in turn, activates MAPK, resulting in an increase in nitric oxide synthase (NOS) expression in pulmonary artery endothelial cells (PAECs). The present study was designed to investigate the pathway by which ANG II activates Src leading to an increase in ERK1/ERK2 phosphorylation and an increase in NOS protein in PAECs. Transfection of PAECs with Gαi3dominant negative (DN) cDNA blocked the ANG II-dependent activation of Src, ERK1/ERK2 phosphorylation, and increase in NOS expression. ANG II stimulated an increase in tyrosine phosphorylation of sequence homology of collagen (Shc; 15 min) that was prevented when PAECs were pretreated with 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolo-[3,4-d]pyrimidine (PP2), a Src inhibitor. ANG II induced a Src-dependent association between Shc and growth factor receptor-bound protein 2 (Grb2) and between Grb2...

Aging Cell, 2007

Vascular aging is characterized by increased oxidative stress, impaired nitric oxide (NO) bioavai... more Vascular aging is characterized by increased oxidative stress, impaired nitric oxide (NO) bioavailability and enhanced apoptotic cell death. The oxidative stress hypothesis of aging predicts that vascular cells of longlived species exhibit lower production of reactive oxygen species (ROS) and/or superior resistance to oxidative stress. We tested this hypothesis using two taxonomically related rodents, the white-footed mouse (Peromyscus leucopus) and the house mouse (Mus musculus), that show a more than twofold difference in maximum lifespan potential (MLSP = 8 and 3.5 years, respectively). We compared interspecies differences in endothelial superoxide () and hydrogen peroxide (H 2 O 2) production, NAD(P)H oxidase activity, mitochondrial ROS generation, expression of pro-and antioxidant enzymes, NO production, and resistance to oxidative stress-induced apoptosis. In aortas of P. leucopus , NAD(P)H oxidase expression and activity, endothelial and H 2 O 2 production, and ROS generation by mitochondria were less than in mouse vessels. In P. leucopus , there was a more abundant expression of catalase, glutathione peroxidase 1 and hemeoxygenase-1, whereas expression of Cu/Zn-SOD and Mn-SOD was similar in both species. NO production and endothelial nitric oxide synthase expression was greater in P. leucopus. In mouse aortas, treatment with oxidized low-density lipoprotein (oxLDL) elicited substantial oxidative stress, endothelial dysfunction and endothelial apoptosis (assessed by TUNEL assay, DNA fragmentation and caspase 3 activity assays). According to our prediction, vessels of P. leucopus were more resistant to the proapoptotic effects of oxidative stressors (oxLDL and H 2 O 2). Primary fibroblasts from P. leucopus also exhibited less H 2 O 2-induced DNA damage (comet assay) than mouse cells. Thus, increased lifespan potential in P. leucopus is associated with a decreased cellular ROS generation and increased oxidative stress resistance, which accords with the prediction of the oxidative stress hypothesis of aging.