scholarly journals High Glucose Induced Smad3 Linker Phosphorylation and CCN2 Expression is Inhibited by Dapagliflozin in a Diabetic Tubule Epithelial Cell Model

2021 ◽  
Author(s):  
Xinlu Pan ◽  
Mysore Phanish ◽  
Deborah Baines ◽  
Mark E Dockrell
Keyword(s):  
Proximal Tubule ◽  
Cell Model ◽  
Gamma Glutamyl Transferase ◽  
Diabetic Kidney ◽  
Sodium Glucose Cotransporter ◽  
Sglt2 Inhibition ◽  
Elevated Glucose ◽  
Glutamyl Transferase ◽  
Ccn2 Expression ◽  
Tgf Β1

In the kidney glucose is  filtered by the glomerulus and reabsorbed by sodium glucose cotransporter 2 (SGLT2) in the early proximal tubule. Human proximal tubule epithelial cells (PTECs) undergo pathological changes seen in Diabetic Kidney Disease (DKD) in response to elevated glucose. We developed a model of DKD using primary human PTECs with exposure to high D-glucose and TGF-β1 and propose a role for SGLT2 inhibition in regulating fibrosis. Western blotting was performed to detect cellular and secreted proteins. qPCR was used to detect CCN2 RNA. Gamma glutamyl transferase (GT) activity staining was performed to confirm PTEC phenotype. SGLT2 and ERK inhibition on D-glucose, 25mM, and TGF-β1, 0.75ng/ml, treated cells was explored using dapagliflozin and U0126, respectively. Only the combination of high D-glucose and TGF-β1 treatment significantly upregulated CCN2 RNA and protein expression. This increase was significantly ameliorated by dapagliflozin. High D-glucose treatment raised phospho ERK which was also inhibited by dapagliflozin. TGF-β1 increased cellular phosphoSSXS-Smad3 serines 423 and 425, with and without high D-glucose. Glucose alone had no effect. Smad3 serine 204 phosphorylation was significantly raised by a combination of high D-glucose+TGF-β1; this was significantly reduced by SGLT2 and MEK inhibition. We show that high D-glucose and TGF-β1 are both required for CCN2 expression. This treatment also caused Smad3 linker phosphorylation. Both outcomes were inhibited by dapagliflozin. We have identified a novel SGLT2 –ERK mediated promotion of TGF-β1/Smad3 signalling inducing pro-fibrotic growth factor secretion. Our data evinces support for substantial renoprotective benefits of SGLT2 inhibition in the diabetic kidney.

scholarly journals Effect of nanopolysaccharide (BSEPS) from Bacillus subtilis sp. on thioacetamide-induced liver fibrosis in rats

2019 ◽  
Vol 43 (1) ◽  
Author(s):  
Manal G. Mahmoud ◽  
Mohsen S. Asker ◽  
Mohamed E. El Awady ◽  
Amal I. Hassan ◽  
Nadia A. R. Zaharan ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Liver Fibrosis ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Periodate Oxidation ◽  
Hepatic Tissue ◽  
Albino Rats ◽  
Gamma Glutamyl Transferase ◽  
Glutamyl Transferase ◽  
Tgf Β1

Abstract Background Nanomedicine contributes to the efficiency of pharmacological treatments and progresses rapidly. The present study was designed to produce exopolysaccharide (BSEPS) from Bacillus subtilis sp. strain reported in our previous study was further characterized, and its BSEPS for synthesis of the nanoparticle Ag-BSEPS using microwave heating to determine the possible effects of a prepared solution containing Ag-BSEPS versus thioacetamide (TAA) evoked liver fibrosis in Wister albino rats. Nanoparticles with silver (Ag) core have been synthesized in an aqueous solution after exposure of BSEPS to periodate oxidation. Animals were split into four groups: I - control rats, water ad libitum for 6 weeks; II - rats were injected with TAA 200 mg/kg-1 3 times/week for 4 weeks IP; III - Ag-BSEPS 100 mg/kg-1 IP twice a week for 6 weeks; and IV - TAA, as group II followed by Ag-BSEPS as group III. The antifibrotic effects of Ag-BSEPS were appraised by determining different hepatotoxicity indices, oxidative stress, and inflammatory and liver fibrosis markers. Results Nanoparticles were obtained with a diameter size range of 50–100 nm characterized by SEM and TEM without using any harmful reagents. Results evinced considerably reduced activity of liver functions such as transaminases (AST, ALT), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) in the group which received TAA followed by Ag-BSEPS compared to the other group which received only TAA. In the current results, the administration of Ag-BSEPS showed an improvement in the proinflammatory cytokines. On the contrary, the antioxidant enzymes in liver homogenates revealed significant improvement (concentration of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), and catalase (CAT) increases) in animals with TAA-induced liver damage followed by Ag-BSEPS. Moreover, the activities of the fibrotic markers transforming growth factor-beta 1(TGF-β1) and type III pro-collagen (PCIII) were increased in liver tissues in the group which was given TAA alone as compared to the controls. The percentage of fibrosis of hepatic tissue had a positive correlation with the levels of PCIII and TGF-β1, followed by Ag-BSEPS compared to the TAA group without nanocomposite treatment. Microscopic examinations revealed inhibitory effects of Ag-BSEPS on inflammatory changes and deterrent of liver fibrosis. Conclusion It was suggested that the biochemical and histological amelioration observed in Ag-BSEPS (100 mg/kg-1 twice a week for 6 weeks) treated the fibrotic rats.

Glutathione protects signal transduction in type II cells under oxidant stress

1994 ◽  
Vol 266 (2) ◽  
pp. L172-L177 ◽  
Author(s):  
L. A. Brown
Keyword(s):  
Signal Transduction ◽  
Membrane Lipids ◽  
Cell Model ◽  
Oxidant Stress ◽  
Gamma Glutamyl Transferase ◽  
Type Ii Cells ◽  
Type Ii ◽  
Oxidant Injury ◽  
Surfactant Secretion ◽  
Glutamyl Transferase

Brief exposure of type II cells to 100 microM t-butyl hydroperoxide (tBOOH) inhibits agonist-induced surfactant secretion and second messenger generation presumably through the oxidation of membrane lipids. Since glutathione (GSH) reduces lipid peroxides and protects type II cells from oxidant injury as determined by crude indicators, then GSH should also protect signal transduction. In the current study, tBOOH inhibited ATP-induced adenosine 3',5'-cyclic monophosphate and inositol trisphosphate generation and surfactant secretion. Stimulation of surfactant secretion by forskolin or phorbol acetate was also inhibited by tBOOH. Pretreatment with GSH (1 mM) blocked the tBOOH inhibition. This protection occurred in the presence of gamma-glutamyl transferase and gamma-glutamylcysteine synthetase inhibitors and suggested GSH was transported as an intact molecule. GSH protection was blocked by gamma-L-glutamyl-L-glutamate, an agent that blocks GSH transport. Protection of surfactant secretion and signal transduction was also provided by the constitutive amino acids but not if GSH synthesis was blocked. In the cultured type II cell model, GSH transport and synthesis protected signal transduction and, subsequently, surfactant secretion against oxidant injury.

scholarly journals Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron

2016 ◽  
Vol 310 (11) ◽  
pp. F1269-F1283 ◽  
Author(s):  
Anita T. Layton ◽  
Volker Vallon ◽  
Aurélie Edwards
Keyword(s):  
Oxygen Consumption ◽  
Proximal Tubule ◽  
Renal Cortex ◽  
Rat Kidney ◽  
Sodium Glucose Cotransporter ◽  
Collecting Ducts ◽  
Sglt2 Inhibition ◽  
Glucose Excretion ◽  
Water And Solute Transport ◽  
Do So

Diabetes increases the reabsorption of Na+ (TNa) and glucose via the sodium-glucose cotransporter SGLT2 in the early proximal tubule (S1-S2 segments) of the renal cortex. SGLT2 inhibitors enhance glucose excretion and lower hyperglycemia in diabetes. We aimed to investigate how diabetes and SGLT2 inhibition affect TNa and sodium transport-dependent oxygen consumption [Formula: see text] along the whole nephron. To do so, we developed a mathematical model of water and solute transport from the Bowman space to the papillary tip of a superficial nephron of the rat kidney. Model simulations indicate that, in the nondiabetic kidney, acute and chronic SGLT2 inhibition enhances active TNa in all nephron segments, thereby raising [Formula: see text] by 5–12% in the cortex and medulla. Diabetes increases overall TNa and [Formula: see text] by ∼50 and 100%, mainly because it enhances glomerular filtration rate (GFR) and transport load. In diabetes, acute and chronic SGLT2 inhibition lowers [Formula: see text] in the cortex by ∼30%, due to GFR reduction that lowers proximal tubule active TNa, but raises [Formula: see text] in the medulla by ∼7%. In the medulla specifically, chronic SGLT2 inhibition is predicted to increase [Formula: see text] by 26% in late proximal tubules (S3 segments), by 2% in medullary thick ascending limbs (mTAL), and by 9 and 21% in outer and inner medullary collecting ducts (OMCD and IMCD), respectively. Additional blockade of SGLT1 in S3 segments enhances glucose excretion, reduces [Formula: see text] by 33% in S3 segments, and raises [Formula: see text] by <1% in mTAL, OMCD, and IMCD. In summary, the model predicts that SGLT2 blockade in diabetes lowers cortical [Formula: see text] and raises medullary [Formula: see text], particularly in S3 segments.

scholarly journals Sex-specific Effects of SGLT2 Inhibition in a Kidney with Reduced Nephron Number: Modeling and Analysis

2021 ◽  
Author(s):  
Anita Layton
Keyword(s):  
Kidney Disease ◽  
Kidney Function ◽  
Diabetic Kidney Disease ◽  
Sglt2 Inhibitors ◽  
Male And Female ◽  
Renal Effects ◽  
Diabetic Kidney ◽  
Sodium Glucose Cotransporter ◽  
Patients With Diabetes ◽  
Sglt2 Inhibition

The kidney plays an essential role in regulating the homeostasis of electrolytes, acid-base species, and fluids. Kidney structure and function are significantly affected in diabetes. These pathophysiological changes include glomerular hyperfiltration and tubular hypertrophy, and ultimately leading to diabetic kidney disease. A class of medications that have shown promise in slowing the progression to diabetic kidney disease are the sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 inhibitors target Na+ and glucose reabsorption along the proximal convoluted tubule, enhance urinary glucose, Na+ and fluid excretion, and lower hyperglycemia in diabetes. We postulate that both diabetes-induced and SGLT2 inhibition-induced changes in kidney may exhibit significant sex differences, because the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules, and (iii) study how those renal effects are altered in uninephrectomy. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes and/or uninephredctomy. The simulation results indicate that by inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis.

scholarly journals Activities of Proximal Tubule Enzymes In Urine of Patients Treated With Gentamicin

2007 ◽  
Vol 26 (1) ◽  
pp. 46-50 ◽  
Author(s):  
Biljana Davidović ◽  
Jelica Predojević-Samardžić ◽  
Snežana Uletilović ◽  
Dragana Malčić ◽  
Živko Saničanin
Keyword(s):  
Proximal Tubule ◽  
Aminoglycoside Antibiotic ◽  
Treated Group ◽  
Proximal Tubules ◽  
Urine Samples ◽  
Control Group ◽  
Gamma Glutamyl Transferase ◽  
Gentamicin Treatment ◽  
Alanine Aminopeptidase ◽  
Glutamyl Transferase

Activities of Proximal Tubule Enzymes In Urine of Patients Treated With Gentamicin The activities of the enzymes dominantly localized within the proximal tubules, such as alanine aminopeptidase (AAP), gamma-glutamyl transferase (GGT) and Nacetyl-beta-D-glucosaminidase (NAG), were measured in 12-h urine samples of patients suffering from Gram-negative infections and i.v. treated with gentamicin with the aim of determining the nephrotoxicity of this aminoglycoside antibiotic. The examined groups consisted of 3 - 10 years old children of both sexes, gentamicin-treated, and the control group, each including 30 patients. Urine samples were collected and analyzed five days before the gentamicin application and during the following 10 days of gentamicin treatment (a single i.v. injection per day in the dose of 2.5 mg/kg b.w.). Significant differences in the AAP and GGT activities expressed in U/mmol creatinine were observed between the gentamicin-treated group and the controls already on day 2 (p < 0.05) of the treatment, as well as in the activity of NAG on day 8 (p < 0.01) of the therapy. From these results it can be concluded that even standard gentamicin doses expressed nephrotoxic effects. Statistically significantly increased AAP and GGT activities in the gentamicin-treated group of children recorded already on the 2nd day of treatment demonstrate that these two enzymes represent extremely sensitive indicators of nephrotoxicity. On the other hand, statistically significantly increased NAG activity observed in the gentamicin-receiving group points to more severe gentamicin-provoked injuries of proximal tubules.

Recovery from LCDD-associated Severe Liver Cholestasis: a Case Report and Literature Review

2016 ◽  
Vol 25 (1) ◽  
pp. 99-103 ◽  
Author(s):  
Benoit Brilland ◽  
Johnny Sayegh ◽  
Anne Croue ◽  
Frank Bridoux ◽  
Jean-François Subra ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Intrahepatic Cholestasis ◽  
Relevant Literature ◽  
Gamma Glutamyl Transferase ◽  
Light Chain Deposition Disease ◽  
Deposition Disease ◽  
Uncommon Presentation ◽  
Light Chain Deposition ◽  
Glutamyl Transferase

Light chain deposition disease (LCDD) is a rare multisystemic disorder associated with plasma cell proliferation. It mainly affects the kidney, but liver and heart involvement may occur, sometimes mimicking the picture of systemic amyloidosis. Liver disease in LCDD is usually asymptomatic and exceptionally manifests with severe cholestatic hepatitis. We report the case of a 66-year-old female with κ-LCDD and cast nephropathy in the setting of symptomatic multiple myeloma who, after a first cycle of bortezomib-dexamethasone chemotherapy, developed severe and rapidly worsening intrahepatic cholestasis secondary to liver κ-light chain deposition. Intrahepatic cholestasis was attributed to LCDD on the basis of the liver histology and exclusion of possible diagnoses. Chemotherapy was maintained and resulted in progressive resolution of cholestasis. We report here an uncommon presentation of LCDD, with prominent liver involvement that fully recovered with bortezomib-based chemotherapy, and briefly review the relevant literature. Abbreviations: AKI: Acute kidney injury; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CMV: Cytomegalovirus; EBV: Epstein–Barr virus; GGT: gamma-glutamyl transferase; HSV: Herpes simplex virus; LC: light chain; LCDD: Light chain deposition disease; MIDD: Monoclonal immunoglobulin deposition disease; MM: Multiple myeloma.

Evaluation of Hematological and Biochemical Changes in Dromedary Camel during the Different Stages of Lactation

2020 ◽  
Vol 21 (3) ◽  
pp. 121-124
Author(s):  
Ahmed El-Sayed
Keyword(s):  
Organic Phosphorus ◽  
Hemoglobin Concentration ◽  
Controlled Study ◽  
Mean Corpuscular Hemoglobin ◽  
Dromedary Camel ◽  
Gamma Glutamyl Transferase ◽  
Corpuscular Hemoglobin ◽  
Stage Of Lactation ◽  
Group 2 ◽  
Glutamyl Transferase

Objective: To assess the potential hematobiochemical alterations in healthy dromedary camel during the different stages of lactation. Design: Randomized controlled study. Animals: Fifteen healthy female dromedary camels, with mean body weight of 499.6 kg and mean age of 20 years. Procedures: Camels were categorized into 3 groups' according to their stage of lactation: group 1, early lactation (1-3 months), group 2, mid-lactation (four-6 months) and group3, late lactation (≥ 7 months). Blood samples were collected from every animals for hematological and biochemical evaluation. Results: Total erythrocyte count (TEC), hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), total leukocytes (TLC), lymphocytes, neutrophils, monocytes, Calcium, glucose, aspartate aminotransferase (AST), alanine transaminase (ALT), gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP) confirmed significant (p < 0.05) variation between different stages of lactation. However, non-notable (p > 0.05) dissimilarity were located in packed cell volume (PCV), mean corpuscular hemoglobin concentration (MCHC), in organic phosphorus (P), magnesium (Mg), cholesterol, total protein (TP), albumen, globulin, blood urea nitrogen (BUN) and creatinine kinase (CK) in the course of different ranges of lactation, Conclusion and clinical relevance: The results of this investigation may be useful as reference guide for dromedary camel to evaluate the metabolic health status at different stages of lactation.

Interactions Between Dental Composite Resins and Saliva A comparative biochemical in vitro study

2019 ◽  
Vol 56 (3) ◽  
pp. 529-533
Author(s):  
Mihaela Pantea ◽  
Diana Andreea Ighigeanu ◽  
Alexandra Totan ◽  
Maria Greabu ◽  
Daniela Miricescu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
In Vitro Study ◽  
Composite Resins ◽  
Vitro Study ◽  
Dental Composite ◽  
Gamma Glutamyl Transferase ◽  
Specific Protocol ◽  
Dental Composite Resins ◽  
Glutamyl Transferase

This in vitro study analyses the biochemical interaction between saliva and three types of dental composite resins (a direct resin, an indirect resin and a dual-cure resin used for cementation of indirect dental restorations). The resin samples were obtained following a specific protocol and in line with the producers� recommendations; the resin samples were incubated with saliva samples collected from 19 healthy volunteers. The obtained results showed that the tested composite resins did not produce significant changes in oxidative stress parameters that were analysed (albumin, uric acid, GGT / gamma glutamyl transferase, OXSR-1 / oxidative stress responsive kinase 1) and do not influence the inflammatory salivary status reflected by the levels of IL-6 - an inflammatory marker.

scholarly journals Biochemical abnormalities in COVID-19: a comparison of white versus ethnic minority populations in the UK

2021 ◽  
pp. jclinpath-2021-207446
Author(s):  
David R Taylor ◽  
Devon Buchanan ◽  
Wiaam Al-Hasani ◽  
Jessica Kearney ◽  
Tina Mazaheri ◽  
...  
Keyword(s):  
Intensive Care ◽  
Ethnic Minority ◽  
Ethnic Minorities ◽  
Troponin T ◽  
Minority Group ◽  
Patient Data ◽  
Minority Population ◽  
Gamma Glutamyl Transferase ◽  
Ethnic Minority Population ◽  
Glutamyl Transferase

AimsPublic Health England has identified that in COVID-19, death rates among ethnic minorities far exceeds that of the white population. While the increase in ethnic minorities is likely to be multifactorial, to date, no studies have looked to see whether values for routine clinical biochemistry parameters differ between ethnic minority and white individuals.MethodsBaseline biochemical data for 22 common tests from 311 SARS-CoV-2 positive patients presenting to hospital in April 2020 in whom ethnicity data were available was retrospectively collected and evaluated. Data comparisons between ethnic minority and white groups were made for all patient data and for the subset of patients subsequently admitted to intensive care.ResultsWhen all patient data were considered, the ethnic minority population had statistically significant higher concentrations of C reactive protein (CRP), aspartate aminotransferase and gamma-glutamyl transferase, while troponin T was higher in the white group. A greater proportion of ethnic minority patients were subsequently admitted to intensive care, but when the presenting biochemistry of this subset of patients was compared, no significant differences were observed between ethnic minority and white groups.ConclusionOur data show for the first time that routine biochemistry at hospital presentation in COVID-19 differs between ethnic minority and white groups. Among the markers identified, CRP was significantly higher in the ethnic minority group pointing towards an increased tendency for severe inflammation in this group.

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