Humans ; Liver ; cytology ; metabolism ; Liver Diseases ; metabolism ; pathology ; therapy ; Receptors, Angiotensin ; metabolism ; Receptors, Cell Surface ; metabolism ; Receptors, Endothelin ; metabolism ; Receptors, Vasopressin ; metabolism

OBJECTIVETo review the advances of studies on vitamin D receptor and its role in the pathogenesis of diabetic nephropathy.

DATA SOURCESA comprehensive search of the PubMed literatures without restriction on the publication date was carried out using keywords such as vitamin D receptor and diabetic nephropathy.

STUDY SELECTIONArticles related to vitamin D receptor and diabetic nephropathy were selected and carefully analyzed.

RESULTSThe ligands as well as construction and tissue distribution of vitamin D receptor were summarized. Pathogenesis of diabetic nephropathy was analyzed. The mechanisms underlying the renoprotective role of vitamin D receptor including inhibition of renin-angiotensin system, anti-inflammation, anti-fibrosis and the reduction of proteinuria were reviewed. Mounting evidences from animal and clinical studies have suggested that vitamin D therapy has beneficial effects on the renal systems and the underlying renoprotective mechanisms of the vitamin D receptor-mediated signaling pathways is a hot research topic.

CONCLUSIONOur study suggests that vitamin D receptor has a great potential for preventing the progression of diabetic nephropathy via multiple mechanisms.

Animals ; Diabetic Nephropathies ; metabolism ; Humans ; Proteinuria ; metabolism ; Receptors, Calcitriol ; metabolism ; Renin-Angiotensin System ; physiology

OBJECTIVETo investigate the changes of angiotensin II (Ang II) and its receptors in male rats with diabetic erectile dysfunction (DED) so as to study its effects.

METHODSOut of 40 male SD rats, 30 were taken at random for diabetic models. After 8 weeks, the rats with erectile dysfunction were selected from these models. All the rats were divided into 3 groups: control ( n = 10), diabetes mellitus( DM, n = 9) and DED (n = 8). For each rat, the Ang II levels in the blood and homogenate prepared from part of the isolated penile tissues were determined respectively, and the Ang II receptors of the rest of the penile tissues were analyzed through immunohistochemical (IHC) assay.

RESULTSCompared with the control group, Ang II levels in the blood and penile tissues in the DM group, and that in the blood of the DED group were very high and the differences were statistically significant (P < 0.05). Ang II in the penile tissues of the DED increased sharply (P < 0.01). The receptors of Ang II changed contrariwise to the level of Ang ll.

CONCLUSIONAng II may play an important role in the pathogenesis of DED, and the Ang II antagonist or inhibitor of the angiotensin-converting enzyme (ACEI) may become a therapeutic method for DED in the future.

Angiotensin II ; blood ; metabolism ; Animals ; Diabetes Complications ; blood ; metabolism ; Erectile Dysfunction ; blood ; etiology ; metabolism ; Immunohistochemistry ; Male ; Penis ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Angiotensin ; blood ; metabolism

OBJECTIVEThis study was undertaken to observe the change in the local level of angiotensin II (Ang II) and the expression of its corresponding receptors AT1 and AT2 during wound healing, and explore the possible role of Ang II in wound healing .

METHODSA model of full-thickness cutaneous wound was developed on the back of C57/BL6 mice. Specimens were taken from the wound of each mouse on the day 0, 1, 3, 5, 7, 9, 11, 13 and 15 after wounding. The change in the generation of Ang II in wounded tissue during the healing process was detected with ELISA. The proliferation and the apoptosis of cells were detected by bromodeoxyuridine (Brdu) and terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling (TUNEL) method in wounded skin during the healing process, respectively. The cellular localization and the mRNA level change of Ang II receptors in wounded tissue during healing were detected with immunostaining and RT-PCR.

RESULTSAng II produced in wounded skin was increased in the first 7 days to reach the peak, and then gradually decreased during wound healing. BrdU labeling index was increased gradually in the first 7 days to reach the peak, and then gradually decreased during wound healing. The number of TUNEL-positive cells was increased slowly in the first 7 days after wounding. The increase in the number of TUNEL-positive cells was more markedly after epithelization of the wound. In normal mice, AT1 and AT2 receptor were found positively expressed in the whole epidermal layer, while positive expression was only found in the endothelial cells of the capillary vessels within the dermal layer, and positive expression was also found in appendages of the skin, i. e. hair follicle, sweat gland and sebaceous gland respectively. Positive staining signal of both AT1 and AT2 receptors were increased in the first 7 days to reach the peak, then gradually decreased. Expression of AT2R was increased again following the epithelization of wound. The result of RT-PCR showed that the expression of both AT1 and AT2 receptors was detectable, and AT1 receptor was increased in the first 7 days to the peak, and then gradually decreased during wound healing, while AT2 receptor expression reached its peak value on day 7, then gradually decreased, and increased again following the epithelization of wound.

CONCLUSIONSThese results indicate that Ang II participate in wound repair and related to remolding in the late stage of wound healing through the change in production of angiotensin II and expression of AT1 and AT2 receptors. AT1 receptor might be closely associated with cell proliferation, while AT2 receptor might play a role in cell apoptosis and remolding during wound healing.

Angiotensin II ; genetics ; metabolism ; Animals ; Apoptosis ; Cell Proliferation ; Male ; Mice ; Mice, Inbred C57BL ; RNA, Messenger ; genetics ; Receptors, Angiotensin ; genetics ; metabolism ; Skin ; injuries ; metabolism ; pathology ; Wound Healing ; physiology

With the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) all over the world, there is an increasing number of children with such infection. Angiotensin-converting enzyme 2 (ACE2), one of the binding sites for SARS-CoV-2 infection in humans, can bind to viral spike proteins, allowing transmembrane serine protease (TMPRSS2) to activate S-protein to trigger infection and induce the production of various inflammatory factors such as interleukin-1, interferon-l, and tumor necrosis factor. Compared with adults, children tend to have lower expression levels of ACE2 and TMPRSS2, which are presumed to be associated with milder symptoms and fewer cases in children. The article summarizes the research advances in the role of ACE2 during SARS-CoV-2 infection, in order to help understand the pathogenic mechanism of SARS-CoV-2 and provide a reference for better development of drugs and vaccines to prevent and treat coronavirus disease 2019 in children.
Angiotensin-Converting Enzyme 2/metabolism* ; COVID-19 ; Child ; Humans ; Receptors, Virus/metabolism* ; SARS-CoV-2 ; Serine Endopeptidases/metabolism*

Previously, we reported that high glucose enhanced cytokine-induced nitric oxide (NO) production by rat mesangial cells (MCs), and that the enhanced expression of the iNOS pathway may promote extracellular matrix accumulation by MCs. The present study was designed to examine whether the iNOS pathway is pathologically altered in experimental diabetic nephropathy, and whether therapy with angiotensin converting enzyme (ACE) inhibitor (imidapril: I) or angiotensin II type I receptor (AT1) blocker (L-158,809: L), ameliorates these changes. Male Sprague-Dawley rats were injected with diluent (control: C) or streptozotocin. At sacrifice after 4, 8 and 12 weeks, rats underwent either a 4 hour placebo or an intraperitoneal lipopolysaccharide (LPS, 2 mg/kg) challenge. Systolic blood pressure (SBP) and urinary protein excretion (UPE) increased significantly in diabetic (D) rats compared with C. The basal expression of glomerular iNOS mRNA was increased in D rats compared with that of C rats, by reverse- transcription (RT)-polymerase chain reaction (PCR), whereas there was no significant difference in the level of protein by Western blot analysis. Upon LPS stimulation, the iNOS mRNA and protein expression was significantly elevated in D rats. In D rats, this up-regulation, of LPS-stimulated iNOS expression, was equally ameliorated both by I and L in mRNA and protein levels. From immunohistochemistry (IHC), there was a negative staining for the iNOS within the glomeruli of five C rats without LPS treatment, but one of four rats, with LPS treatment, showed minimal iNOS staining in the glomeruli. In D rats, the glomerular mesangium and podocytes were positive for iNOS in each of three out of five rats with, and without, LPS treatment. In conclusion, LPS-stimulated glomerular iNOS expression was enhanced in diabetic pnephropathy, and the activation of angiotensin II may play a role in this enhancement.
Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Animal ; Kidney Glomerulus/*drug effects/*enzymology ; Lipopolysaccharides/*pharmacology ; Male ; Nitric-Oxide Synthase/*metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Angiotensin/antagonists & inhibitors

AIM AND METHODSTo investigate the role of modulation by angiotensin AT1 receptor in sodium and water excretion induced by cholinergic agonist carbachol. Tyrosine hydroxylase immunoreactivity (TH-IR) in hypothalamus were also observed.

RESULTSThe natriuretic and diuretic effect induced by carbachol (CBC) were partially inhibited by pretreatment of losartan, a specific blocker of angiotensin AT1 receptor (P < 0.05). Immunohistochemistry showed that both TH-IR density and number of TH-IR positive neurons were markedly increased in PaPo, Arc, Pe and AHP of hypothalamus at 40 min after carbachol administration, as compared with NS group (P < 0.05). However, in losartan pretreated group, the number and the density of TH-IR were significantly decreased in such nuclei mentioned above except PaPo.

CONCLUSIONThe results above suggest that brain AT1 receptor appears to be involved in mediating natriuresis induced by cholinergic stimulus. The blockade of AT1 receptor may down regulate the excitability of adrenergic neurons in Arc, Pe and AHP induced by CBC. We postulate that brain adrenergic and angiotensinergic pathway get involved in natriuresis induced by brain cholinergic stimulus together. Moreover, angiotensinergic neurons may influence the activity of adrenergic neurons in hypothalamus.

Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; Animals ; Brain ; metabolism ; Carbachol ; pharmacology ; Losartan ; pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1 ; metabolism ; Receptors, Cholinergic ; metabolism ; Sodium ; metabolism ; Water ; metabolism

OBJECTIVETo investigate the mechanism of a novel angiotensin II type 1 receptor-associated protein (ATRAP) interfering with angiotensin II type 1 (AT1) receptor-mediated vascular smooth muscle cell (VSMC) growth and neointimal formation.

METHODSVSMCs isolated from thoracic aorta of adult Sprague-Dawley (SD) rats were used in this study. ATRAP cDNA was subcloned into pcDNA3 vector and then transfected into VSMCs. DNA synthesis and extracellular signal-regulated kinase (ERK) and phospho-ERK expressions in VSMCs were assayed by measurement of 3H thymidine incorporation and Western blotting, respectively. Morphological changes were observed in the balloon injured artery with or without transfection of ATRAP cDNA using 12-week-old male SD rats.

RESULTSATRAP overexpression in VSMCs inhibited angiotensin II (Ang II)-induced 3H thymidine incorporation 48 hours after Ang II stimulation (P < 0.05). In VSMC, Ang II stimulation increased the phosphorylation of ERK, which reached the peak around 60 minutes. The activation of phospho-ERK was significantly decreased by ATRAP (P < 0.05). Neointimal formation was markedly inhibited by ATRAP overexpression in injuried arteries.

CONCLUSIONSThe AT1 receptor-derived activation of ERK plays an essential role in Ang II-induced VSMC growth. The growth inhibitory effects of ATRAP might be due to interfering with AT1 receptor-mediated activation of ERK in VSMC growth and neointimal formation.

Angiotensin II ; pharmacology ; Animals ; Aorta, Thoracic ; cytology ; Cell Division ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Male ; Muscle, Smooth, Vascular ; cytology ; physiology ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1 ; physiology ; Receptors, Angiotensin ; genetics ; physiology ; Transfection ; Tunica Intima ; cytology

OBJECTIVETo determine the biotic effects of angiotensin II (Ang II) on the migration of rat smooth muscle cells (VSMCs) and investigate the mechanisms involved in the development of vascular injury.

METHODSVSMCs isolated from aortic media of Wistar rats and cultured by the modified explant method were adopted. In the presence and absence of Ang II, the expression of Ang II receptor (ATR) and reorganization of the actin cytoskeleton and focal adhesion of VSMCs were studied by an immunocytochemistry technique and fluorocytochemistry technique. Migration assays were performed with a modified Boyden's chamber. The effects of AT(1)R antagonist (CV-11974), AT(2)R antagonist (PD123319) on the aforementioned target were studied.

RESULTSVSMCs migration was stimulated by adding Ang II. The dynamic reorganization of actin cytoskeleton and focal adhesions may be an important mechanism by which Ang II facilitates VSMCs motility. The expression of AT(1)R in VSMCs could be upregulated initially after treatment with Ang II, then decreased gradually. The expression of AT(1)R was downregulated by AT(1)R antagonists. The effect of Ang II on VSMCs migration was mediated by AT(1)R, while AT(2)R had no significant effect.

CONCLUSIONSThe dynamic reorganization of focal adhesions and the actin cytoskeleton is required for Ang II-induced VSMCs migration. This effect is mediated by AT(1)R.

Actins ; drug effects ; metabolism ; Angiotensin II ; pharmacology ; Angiotensin Receptor Antagonists ; Animals ; Benzimidazoles ; pharmacology ; Cell Movement ; drug effects ; Cells, Cultured ; Cytoskeleton ; drug effects ; Dose-Response Relationship, Drug ; Female ; Focal Adhesions ; drug effects ; metabolism ; Imidazoles ; pharmacology ; Immunohistochemistry ; Male ; Muscle, Smooth, Vascular ; cytology ; drug effects ; metabolism ; Pyridines ; pharmacology ; Rats ; Rats, Wistar ; Receptor, Angiotensin, Type 1 ; Receptors, Angiotensin ; metabolism ; Tetrazoles ; pharmacology

BACKGROUNDMany studies have suggested that angiotensin II (Ang II) and its receptors may be involved in the development of asthma. However, the expression of angiotensin II receptors (AGTR) is not clear in the lung tissue of chronic asthmatics. This study was designed to determine the relationship between airway remodeling, dysfunction and the expression of AGTRs in a rat model of asthma.

METHODSRats were sensitized with ovalbumin (OVA) for 2 weeks. Sixty minutes before an inhalation challenge, the rats were pretreated either with valsartan (15, 30, 50 mg x kg(-1) x d(-1)) or saline intragastrically. Then the rats received an OVA challenge for 30 alternative days. Acetylcholine (Ach)-induced bronchoconstriction was measured after the final antigen challenge. White cell counts in bronchoalveolar lavage fluid (BALF) and morphological changes in the airways were then assessed. The levels of transforming growth factor-beta 1 (TGF-beta(1)) and platelet-derived growth factor (PDGF) in BALF were detected by ELISA. The levels of AGTR1 and AGTR2 mRNA and protein in lung tissues were measured by RT-PCR and Western blotting.

RESULTSAGTR1 mRNA and protein levels in repeatedly OVA-challenged rats were significantly increased as compared with negative controls. The AGTR1 mRNA expression versus white cell counts of BALF and airway wall thickness (mainly in small airways) in lungs of chronic antigen-exposed rats were positively correlated. Valsartan decreased the level of AGTR1 in repeatedly OVA-challenged rats. However, AGTR2 mRNA and protein levels in the OVA-challenged rats and high-dose valsartan-treated rats (50 mg x kg(-1) x d(-1)) were also increased. Valsartan significantly decreased inflammatory cell accumulation and attenuated Ach-evoked bronchoconstriction in repeatedly antigen-challenged rats. Valsartan also decreased allergen-induced structural changes in rat airway (including total airway wall thickness and smooth muscle area) and the levels of TGF-beta(1) and PDGF in BALF.

CONCLUSIONSAGTR1 expression is potentially associated with airway remodeling and dysfunction in asthma. Ang II and AGTR1 may participate in airway inflammation and airway remodeling of chronic antigen-exposed rats. Valsartan, a AGTR1 antagonist, could inhibit AGTR1 expression and partially inhibits structural airway changes as well as airway inflammation in chronic OVA-exposed rats.

Angiotensin II Type 1 Receptor Blockers ; pharmacology ; Angiotensin Receptor Antagonists ; Animals ; Asthma ; chemically induced ; genetics ; metabolism ; Blotting, Western ; Bronchoalveolar Lavage Fluid ; chemistry ; Enzyme-Linked Immunosorbent Assay ; Gene Expression ; drug effects ; Lung ; drug effects ; metabolism ; pathology ; Male ; Ovalbumin ; Platelet-Derived Growth Factor ; metabolism ; Rats ; Rats, Wistar ; Receptor, Angiotensin, Type 1 ; genetics ; metabolism ; Receptor, Angiotensin, Type 2 ; genetics ; metabolism ; Receptors, Angiotensin ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tetrazoles ; pharmacology ; Transforming Growth Factor beta1 ; metabolism ; Valine ; analogs & derivatives ; pharmacology ; Valsartan