scholarly journals Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers

2021 ◽  
Vol 22 (23) ◽  
pp. 12629
Author(s):  
Yi Yang ◽  
Kenneth Kowalkowski ◽  
Rita Ciurlionis ◽  
Wayne R. Buck ◽  
Keith B. Glaser ◽  
...  
Keyword(s):  
Morphological Changes ◽  
Clinical Chemistry ◽  
Urinary Biomarkers ◽  
Ultrastructural Changes ◽  
Vegf Receptor ◽  
Cancer Therapies ◽  
Sprague Dawley ◽  
Glomerular Injury ◽  
Vegf Signaling ◽  
Vegf Inhibition

Cancer therapies targeting the vascular endothelial growth factor (VEGF) signaling pathway can lead to renal damage by disrupting the glomerular ultrafiltration apparatus. The objective of the current study was to identify sensitive biomarkers for VEGF inhibition-induced glomerular changes in rats. Male Sprague-Dawley rats were administered an experimental VEGF receptor (VEGFR) inhibitor, ABT-123, for seven days to investigate the correlation of several biomarkers with microscopic and ultrastructural changes. Glomeruli obtained by laser capture microdissection were also subjected to gene expression analysis to investigate the underlying molecular events of VEGFR inhibition in glomerulus. ABT-123 induced characteristic glomerular ultrastructural changes in rats, including fusion of podocyte foot processes, the presence of subendothelial electron-dense deposits, and swelling and loss of fenestrations in glomerular endothelium. The subtle morphological changes cannot be detected with light microscopy or by changes in standard clinical chemistry and urinalysis. However, urinary albumin increased 44-fold as early as Day three. Urinary β2-microglobulin levels were also increased. Other urinary biomarkers that are typically associated with tubular injury were not significantly impacted. Such patterns in urinary biomarkers can provide valuable diagnostic insight to VEGF inhibition therapy-induced glomeruli injuries.

Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus

2003 ◽  
Vol 284 (3) ◽  
pp. L508-L517 ◽  
Author(s):  
Theresa R. Grover ◽  
Thomas A. Parker ◽  
Jeanne P. Zenge ◽  
Neil E. Markham ◽  
John P. Kinsella ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Protein Content ◽  
Ductus Arteriosus ◽  
Late Gestation ◽  
Receptor Protein ◽  
Vegf Receptor ◽  
Fetal Life ◽  
Vegf Expression ◽  
Vegf Signaling ◽  
Vegf Inhibition

Although vascular endothelial growth factor (VEGF) plays a vital role in lung vascular growth in the embryo, its role in maintaining endothelial function and modulating vascular structure during late fetal life has not been studied. We hypothesized that impaired lung VEGF signaling causes pulmonary hypertension, endothelial dysfunction, and structural remodeling before birth. To determine whether lung VEGF expression is decreased in an experimental model of persistent pulmonary hypertension of the newborn (PPHN), we measured lung VEGF and VEGF receptor protein content from fetal lambs 7–10 days after ductus arteriosus ligation (132–140 days gestation; term = 147 days). In contrast with the surge in lung VEGF expression during late gestation in controls, chronic intrauterine pulmonary hypertension reduced lung VEGF expression by 78%. To determine whether VEGF inhibition during late gestation causes pulmonary hypertension, we treated fetal lambs with EYE001, an aptamer that specifically inhibits VEGF165. Compared with vehicle controls, EYE001 treatment elevated pulmonary artery pressure and pulmonary vascular resistance by 22 and 50%, respectively, caused right ventricular hypertrophy, and increased wall thickness of small pulmonary arteries. EYE001 treatment reduced lung endothelial nitric oxide synthase protein content by 50% and preferentially impaired the pulmonary vasodilator response to ACh, an endothelium-dependent agent. We conclude that chronic intrauterine pulmonary hypertension markedly decreases lung VEGF expression and that selective inhibition of VEGF165 mimics the structural and physiological changes of experimental PPHN. We speculate that hypertension downregulates VEGF expression in the developing lung and that impaired VEGF signaling may contribute to the pathogenesis of PPHN.

Functional and morphological changes of the thyroid gland following 5 days of pulsatile TRH stimulation in male rats

1995 ◽  
Vol 146 (2) ◽  
pp. 339-348 ◽  
Author(s):  
C Hoang-Vu ◽  
G Brabant ◽  
H Leitolf ◽  
A von zur Mühlen ◽  
H Dralle ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Morphological Changes ◽  
Dominant Role ◽  
Major Product ◽  
Male Rats ◽  
Ultrastructural Changes ◽  
Sprague Dawley ◽  
Immunogold Staining ◽  
Trh Stimulation

Abstract The aim of the present study was to evaluate in vivo the selective effects of a small increase in plasma TSH levels on thyroid function, proliferation and morphology. Chronically catheterized male Sprague–Dawley rats were stimulated i.v. over 5 days either with TRH (2 μg TRH in 100 μl 0·9% (w/v) NaCl (TRH-P) or the NaCl carrier alone (P), both given as pulses every 2 h. Control groups were cotreated i.v. with 10 μg thyroxine (T4)/100 g body weight per day (TRH-P+T4) starting 2 days before pulsatile stimulation. TSH plasma levels were approximately doubled by TRH-P (P≤0·001), T4 plasma levels significantly increased (P≤0·001) but tri-iodothyronine plasma levels did not change compared with treatment with P. No significant changes between groups were found in thyroid weight and in intrathyroidal iodine content, but the percentage of 5-bromo-2′-desoxyuridinelabelled thyrocytes as a marker of proliferation in TRH-P-treated animals was significantly increased over P or TRH-P+T4 (P≤0·001). Ultrastructural analysis of the thyroid evaluated by electron microscopy revealed a significant increase in the number of lysosomes (P≤0·001). The size of the endoplasmic reticulum (ER) in relation to the cytoplasm was significantly increased when treated with TRH-P compared with P or TRH-P+T4 (P≤0·001). Post-embedding immunogold staining revealed Tg as a major product within ER cisternae. Immunogold labelling was moderate in controls and higher densities of gold particles were obtained in TRH-P-treated animals (P≤0·001). In conclusion, short-term pulsatile TRH stimulation increasing the plasma levels of immunoreactive TSH only twofold is capable of inducing hypertrophy of the thyrocytes by gross ultrastructural changes which are paralleled by an increase in circulating T4. These data underscore the dominant role of TSH on thyroid ultrastructure within the narrow boundaries of normal physiological regulation. Journal of Endocrinology (1995) 146, 339–348

scholarly journals The toxicity of Senecio inaequidens DC.

2007 ◽  
Vol 78 (3) ◽  
Author(s):  
A.F.P. Dimande ◽  
C.J. Botha ◽  
L. Prozesky ◽  
L. Bekker ◽  
G.M. Rosemann ◽  
...  
Keyword(s):  
Pyrrolizidine Alkaloids ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Ultrastructural Changes ◽  
Total Serum ◽  
Sprague Dawley ◽  
Serum Globulin ◽  
Plant Parts ◽  
Senecio Inaequidens ◽  
G Ratio

This study was designed to confirm the toxicity of a plant implicated in an outbreak of poisoning of stock in Frankfort, Free State Province, South Africa. Cows died acutely after being introduced into a camp, where an abundant, green shrublet was noted to be heavily grazed. This plant was subsequently identified as Senecio inaequidens DC. (Asteraceae) by the South African National Biodiversity Institute (SANBI). Extraction and chemical analyses for pyrrolizidine alkaloids (PAs) in Senecio inaequidens revealed the presence of 4 different compounds, namely retrorsine and senecionine (known to be hepatotoxic) and 2 unidentified compounds. The average total PA (free base plus N-oxide) concentration in plant parts of S. inaequidens collected at Frankfort during the outbreak was 0.81 %, compared with the total alkaloid content in the dried, milled S. inaequidens plant material, collected 7 weeks after the outbreak, of only 0.18 %. Male Sprague-Dawley rats (n=4), aged 8-9 weeks, were dosed per os. Each rat received a different dose of the crude Senecio inaequidens extract, ranging from 0.049 mg/g body weight (b.w.) to 0.25 mg/g b.w. No clinical signs were observed in the rat receiving the lowest dose. Rats receiving higher doses showed depression, an unsteady gait, pilo-erection and jaundice, which was particularly noticeable in the ears. Clinical chemistry evaluation revealed an increase in the activities of ALP (except Rat 4), AST and GGT in all animals. Total serum bilirubin, creatinine and urea concentrations were also elevated. All rats had low serum globulin concentrations with an A/G ratio above 1.2. Post mortem examination of the rats revealed marked hepatic lesions. Histopathologically, these changes were characterised by necrosis (variable in extent) of the centrilobular and midzonal hepatocytes (but sparing the portal hepatocytes), with extensive haemorrhage and congestion. Proliferation of the bile ducts, fibrosis and oedema were also present. Ultrastructural changes in affected rats were characterised by margination of chromatin, the presence of numerous autolysosomes in necrotic hepatocytes, intramitochondrial woolly inclusions and changes in the endoplasmic reticulum. A sheep, also dosed with the crude extract, failed to exhibit clinical signs, clinical chemistry aberrations or macroscopic lesions; however, examination of the liver of this sheep revealed histopathological and ultrastructural changes similar, though milder, to those displayed by the rats. Pyrrolizidine alkaloids were extracted from the liver and kidneys of the rats and the sheep. In the case of the sheep, retrorsine was also detected in the lungs, urine and bile.

Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling

2006 ◽  
Vol 290 (2) ◽  
pp. H547-H559 ◽  
Author(s):  
Fabienne Baffert ◽  
Tom Le ◽  
Barbara Sennino ◽  
Gavin Thurston ◽  
Calvin J. Kuo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Basement Membrane ◽  
Kinase Inhibitor ◽  
Vegf Receptor ◽  
Blood Capillaries ◽  
Vegf Signaling ◽  
Adult Mice ◽  
Sequence Of Events ◽  
Vegf Inhibition

The vasculature of the embryo requires vascular endothelial growth factor (VEGF) during development, but most adult blood vessels lose VEGF dependence. However, some capillaries in the respiratory tract and selected other organs of adult mice regress after VEGF inhibition. The present study sought to identify the sequence of events and the fate of endothelial cells, pericytes, and vascular basement membrane during capillary regression in mouse tracheas after VEGF signaling was blocked with a VEGF-receptor tyrosine kinase inhibitor AG-013736 or soluble receptor construct (VEGF Trap or soluble adenoviral VEGFR-1). Within 1 day, patency was lost and fibrin accumulated in some tracheal capillaries. Apoptotic endothelial cells marked by activated caspase-3 were present in capillaries without blood flow. VEGF inhibition was accompanied by a 19% decrease in tracheal capillaries over 7 days and 30% over 21 days. During this period, desmin/NG2-immunoreactive pericytes moved away from regressing capillaries onto surviving vessels. Empty sleeves of basement membrane, left behind by regressing endothelial cells, persisted for about 2 wk and served as a scaffold for vascular regrowth after treatment ended. The amount of regrowth was limited by the number of surviving basement membrane sleeves. These findings demonstrate that, after inhibition of VEGF signaling, some normal capillaries regress in a systematic sequence of events initiated by a cessation of blood flow and followed by apoptosis of endothelial cells, migration of pericytes away from regressing vessels, and formation of empty basement membrane sleeves that can facilitate capillary regrowth.

Basal Lamina Formation in DMBA Induced Mammary Carcinoma

1977 ◽  
Vol 35 ◽  
pp. 534-535
Author(s):  
I. Russo ◽  
J. Saby ◽  
J. Russo
Keyword(s):  
Mammary Carcinoma ◽  
Virgin Female ◽  
Mammary Glands ◽  
Sesame Oil ◽  
Female Rats ◽  
Ultrastructural Changes ◽  
Post Inoculation ◽  
Intermediate Type ◽  
Sprague Dawley ◽  
Intercellular Spaces

It has been previously demonstrated that DMBA-induced rat mammary carcinoma originates in the terminal end bud (TEB) of the mammary gland by proliferation of intermediate type cells (1). The earliest lesion identified is the intraductal proliferation (IDP), which gives rise to intraductal carcinomas. These evolve to cribriform, papillary and comedo types (2). In the present work, we report the ultrastructural changes that take place in the IDP for the formation of a cribriform pattern.Fifty-five-day-old Sprague Dawley virgin female rats were inoculated intra- gastrically with 20 mg 7,12-dimethylbenz(a)anthracene (DMBA) in 1 ml sesame oil. Non-inoculated, age-matched females were used as controls. Mammary glands from both control and experimental rats were removed weekly from the time of inoculation until 86 days post-inoculation. The glands were fixed and processed for electron microscopy (2).The first change observed in IDP's was the widening of intercellular spaces and the secretion of an electron dense material into these spaces (Fig. 1).

Surface ultrastructure of danazol treated rat endometrium: A SEM study

1983 ◽  
Vol 41 ◽  
pp. 556-557
Author(s):  
R.P. Apkarian ◽  
J.S. Sanfilippo
Keyword(s):  
Cross Sections ◽  
Reproductive Tract ◽  
Preliminary Investigation ◽  
Breast Disease ◽  
Distal Segment ◽  
Uterine Horn ◽  
Female Reproductive Tract ◽  
Ultrastructural Changes ◽  
Cycle Phase ◽  
Sprague Dawley

The synthetic androgen danazol, is an isoxazol derivative of ethisterone. It is utilized in the treatment of endometriosis, fibrocystic breast disease, and has a potential use as a contraceptive. A study was designed to evaluate the ultrastructural changes associated with danazol therapy in a rat model. The preliminary investigation of the distal segment of the rat uterine horn was undertaken as part of a larger study intended to elucidate the effects of danazol on the female reproductive tract.Cross-sections (2-3 mm in length) of the distal segment of the uterine horn from sixteen Sprague-Dawley rats were prepared for SEM. Ten rats in estrus served as controls and six danazol treated rats were noted to have alterations of the estrus cycle i.e. a lag in cycle phase or noncycling patterns. Specimens were fixed in 3% glutaraldehyde in 0.05M phosphate buffer containing CaCl2 at pH 7.0-7.4 and chilled to 4°C. After a brief wash in distilled water, specimens were passed through a graded series of ethanol, critical point dryed in CO2 from absolute ethanol, and coated with 6nm Au. Observations were made with an IS1-40 SEM operated at 15kV.

Ultrastructural Effects of Acute Kepone Treatment in Rats

1976 ◽  
Vol 34 ◽  
pp. 286-287
Author(s):  
Richard L. Klein ◽  
Åsa K. Thureson-Klein ◽  
Harihara M. Mehendale
Keyword(s):  
Neurological Disorders ◽  
Corn Oil ◽  
Preliminary Investigation ◽  
Reproductive Capacity ◽  
Ultrastructural Changes ◽  
Lipid Deposition ◽  
Severe Toxicity ◽  
Sprague Dawley ◽  
Ether Anesthesia ◽  
Sprague Dawley Rats

KeponeR (decachlorooctahydro-1,3,4-metheno-2H-cyclobuta[cd]pentalen-2-one) is an insecticide effective against ants and roaches. It can cause severe toxicity in fishes, birds, rodents and man. Prominent effects include hepatic lipid deposition and hypertrophy, impairment of reproductive capacity and neurological disorders. Mitochondrial oligomycin-sensitive Mg2+-ATPase is also inhibited. The present study is a preliminary investigation of tissue ultrastructural changes accompanying physiological signs of acute toxicity, which after two days treatment include: pronounced hypersensitivity and tremor, various degrees of anorexia and adipsia, and decreased weight gain.Three different series of adult male Sprague-Dawley rats (Charles River or CD-I) were treated by intubation with Kepone in corn oil at a dose of 50 mg per kg for 3 successive days or at 200 ppm in food for 8 days. After ether anesthesia, rats were immediately perfused via a cannula in the left ventricle with 4% p-formaldehyde and 0.5% glutaraldehyde in Millonig's phosphate buffer at pH 7.2 for 20-30 min at 22°C.

Ultrastructural Changes in the Mammary Epithelial Cell Population During Neoplastic Development Induced by A Chemical Carcinogen.

1976 ◽  
Vol 34 ◽  
pp. 250-251 ◽  
Author(s):  
J. Russo ◽  
W. Isenberg ◽  
M. Ireland ◽  
I.H. Russo
Keyword(s):  
Mammary Gland ◽  
Cell Population ◽  
Virgin Female ◽  
Histological Change ◽  
Mammary Epithelial ◽  
Female Rats ◽  
Ultrastructural Changes ◽  
Post Inoculation ◽  
Chemical Carcinogen ◽  
Sprague Dawley

The induction of rat mammary carcinoma by the chemical carcinogen DMBA is used as a model for the study of the human disease (1). We previously described the histochemical changes that occur in the mammary gland of DMBA treated animals before the earliest manifested histological change, the intraductal proliferation (IDP), was observed (2). In the present work, we demonstrate that a change in the stable cell population found in the resting mammary gland occurs after carcinogen administration.Fifty-five day old Sprague-Dawley virgin female rats were inoculated intragastrically with 20mg of 7,12-dimethylbenz(a)anthracene (DMBA) in 1ml sesame oil. Non-inoculated, age-matched females were used as controls. Mammary glands from control and inoculated rats were removed weekly from the time of inoculation until 60 days post-inoculation. For electron microscopy, the glands were immersed in Karnovsky's fixative, post-fixed in 1% OsO4, dehydrated, and embedded in an Epon-Araldite mixture. Thick (lμ) sections were stained with 1% toluidine blue and were used for selecting areas for ultrastructural study.

Ultrastructural changes in isolated rat liver perfused with cyclic heptapeptide toxins from norwegian freshwater cyanobacteria (blue-green algae)

1987 ◽  
Vol 45 ◽  
pp. 858-859
Author(s):  
A.S. Dabholkar ◽  
W.W. Carmichael ◽  
K. Berg ◽  
J. Wyman
Keyword(s):  
Ultrastructural Changes ◽  
Sprague Dawley ◽  
Isolated Rat Liver ◽  
Blue Green Algae ◽  
Sprague Dawley Rats ◽  
Cyclic Heptapeptide ◽  
Intracellular Changes ◽  
Oscillatoria Agardhii ◽  
Rat Livers ◽  
Isolated Rat

Intracellular changes in the hepatocytes of isolated rat livers perfused with cyclic heptapeptide toxins are described. The toxins used are 1) -Ala-Leu- β-methyl isoAsp-Arg-ADDA-isoGlu-mdha (M.W. 944) from Microcystis aeruginosa- Lake Akersvatn, Norway; 2) -Ala-Arg-isoAsp-Arg-ADDA-isoGlu-mdha (M.W. 1023) from Oscillatoria agardhii var. - Lake Kolbatnvatn, Norway; 3) -Ala-Arg-isoAsp-Arg-ADDA-isoGlu-dha (M.W. 1009) from Oscillatoria agardhii var. isothrix - Lake Froylandsvatn, Norway. Approximate LD intraperitoneal mouse for the toxins is 50, 500 and 1000 μg/kg respectively.Livers were removed from male Sprague Dawley rats and perfused for 15 min with a blood-free perfusate (50 ml) followed by 60 min with perfusate containing i) 25, 50, or 200 μg of M. aeruginosa toxin ii) 50, 250, 500 or 1000 μg of O. agardhii var. toxin and iii) 1000, 2000, 2500 or 5000 μg of O. agardhii var. isothrix toxin. Control livers were perfused for 75 min with the blood-free perfusate.

Liver Toxicity in Rats Fed A Mixture of Pcb Congeners and 2,3,7,8-Tcdd

1997 ◽  
Vol 3 (S2) ◽  
pp. 51-52
Author(s):  
B.J. Cornell ◽  
A. Singh ◽  
I. Chu
Keyword(s):  
Aromatic Compounds ◽  
Liver Toxicity ◽  
Corn Oil ◽  
Morphological Changes ◽  
Test Substance ◽  
Sprague Dawley ◽  
Morphological Alterations ◽  
Pcb Congeners ◽  
Transmission Electron ◽  
Sprague Dawley Rats

Polyhalogenated aromatic compounds such as polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDDs) continue to be environmental contaminants because of their bioaccumulation in the food chain and high resistance to biodegradation. The current study was undertaken to determine if a mixture of PCB congeners (WHO-IPCS) were interactive with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in producing morphological changes in the rat liver. Both compounds are known to produce a broad range of biochemical and morphological alterations including enzyme induction.Groups (N=5) of female Sprague-Dawley rats were administered TCDD (0, 2.5, 25, 250, 1000 ng/kg bw/day) or PCB (0, 2, 20 μg/kg bw/day) alone, or in combination with each concentration of both compounds. Incorrect concentrations were published in a previous abstract. The test substance was mixed with corn oil and given by gavage at 2 ml/kg daily for 28 days. At the end of the experiment, the rats were killed and liver samples were prepared for transmission electron microscopy.

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