scholarly journals Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 866
Author(s):  
Basma G. Eid ◽  
Thikryat Neamatallah ◽  
Abeer Hanafy ◽  
Hany M. El-Bassossy ◽  
Lenah Binmahfouz ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Transforming Growth Factor Beta ◽  
Cannabinoid Receptors ◽  
Transforming Growth Factor ◽  
Excretion Rate ◽  
Fold Increase ◽  
Albumin Excretion Rate ◽  
Cb1 Receptor ◽  
Protective Effects ◽  
Albumin Excretion

The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action.

Alterations in renal degradation of albumin in early experimental diabetes in the rat: a new factor in the mechanism of albuminuria

1998 ◽  
Vol 95 (1) ◽  
pp. 67-72 ◽  
Author(s):  
Melissa J. BURNE ◽  
Sianna PANAGIOTOPOULOS ◽  
George JERUMS ◽  
Wayne D. COMPER
Keyword(s):  
Size Exclusion Chromatography ◽  
Excretion Rate ◽  
Fold Increase ◽  
Albumin Excretion Rate ◽  
Diabetic Rats ◽  
Size Exclusion ◽  
Intact Protein ◽  
Sprague Dawley ◽  
Albumin Excretion ◽  
Exclusion Chromatography

1.Albumin is normally excreted as a mixture of intact protein and fragments that are produced during renal passage. The purpose of this study was to investigate the ratio of intact versus degraded forms of excreted albumin to ascertain whether changes in this ratio could account for the apparent increase in albumin excretion seen in diabetes, as measured by standard radioimmunoassay techniques. 2.Four-week male Sprague–Dawley rats with streptozotocin-induced diabetes and age-matched control rats were intravenously injected with [3H]albumin. Urine collected over 2 h was analysed by size exclusion chromatography and radioimmunoassay. A standard radioimmunoassay found a 7-fold increase in albumin excretion rate in diabetic rats, whereas there was only a 2-fold increase in albumin excretion (intact plus fragments). Urine analysed by size exclusion chromatography showed severe degradation for control rats (% monomer = 4±2%); in diabetic rats there was a significant amount of monomer albumin excreted, along with moderately degraded and heavily degraded albumin (% monomer = 17±5%). 3.This study has shown that the radioimmunoassay, which specifically detects intact albumin, considerably underestimates the amount of total urinary albumin which consists of intact and degraded material. The increase in albumin excretion rate observed in diabetes as measured by radioimmunoassay is mainly due to a change in the amount of intact albumin excreted and this is specifically due to the inhibition of albumin degradation at a post-glomerular site and not due to the onset of any type of glomerular ‘shunt' pathway.

scholarly journals Role of endocannabinoid CB1 receptors in Streptozotocin-induced uninephrectomised Wistar rats in diabetic nephropathy

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Jayarami Reddy Medapati ◽  
Deepthi Rapaka ◽  
Veera Raghavulu Bitra ◽  
Santhosh Kumar Ranajit ◽  
Girija Sankar Guntuku ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Morphological Changes ◽  
Serum Levels ◽  
Cb1 Receptors ◽  
Protective Effects ◽  
Renal Hypertrophy ◽  
Necrosis Factor Alpha

Abstract Background The endocannabinoid CB1 receptor is known to have protective effects in kidney disease. The aim of the present study is to evaluate the potential agonistic and antagonistic actions and to determine the renoprotective potential of CB1 receptors in diabetic nephropathy. The present work investigates the possible role of CB1 receptors in the pathogenesis of diabetes-induced nephropathy. Streptozotocin (STZ) (55 mg/kg, i.p., once) is administered to uninephrectomised rats for induction of experimental diabetes mellitus. The CB1 agonist (oleamide) and CB1 antagonist (AM6545) treatment were initiated in diabetic rats after 1 week of STZ administration and were given for 24 weeks. Results The progress in diabetic nephropathy is estimated biochemically by measuring serum creatinine (1.28±0.03) (p < 0.005), blood urea nitrogen (67.6± 2.10) (p < 0.001), urinary microprotein (74.62± 3.47) (p < 0.005) and urinary albuminuria (28.31±1.17) (p < 0.0001). Renal inflammation was assessed by estimating serum levels of tumor necrosis factor alpha (75.69±1.51) (p < 0.001) and transforming growth factor beta (8.73±0.31) (p < 0.001). Renal morphological changes were assessed by estimating renal hypertrophy (7.38± 0.26) (p < 0.005) and renal collagen content (10.42± 0.48) (p < 0.001). Conclusions From the above findings, it can be said that diabetes-induced nephropathy may be associated with overexpression of CB1 receptors and blockade of CB1 receptors might be beneficial in ameliorating the diabetes-induced nephropathy. Graphical abstract

scholarly journals The expression of POMC and AgRP in brain and kidney tissues at different stages of diabetic nephropathy rats

2021 ◽  
Vol 1 (1) ◽  
pp. 43-49
Author(s):  
Shasha Liu ◽  
Jingjing Da ◽  
Jiayu Li ◽  
Rong Dong ◽  
Jing Yuan ◽  
...  
Keyword(s):  
Body Weight ◽  
Diabetic Nephropathy ◽  
Blood Glucose ◽  
Urinary Albumin Excretion ◽  
Excretion Rate ◽  
Kidney Tissue ◽  
Albumin Excretion Rate ◽  
Urinary Albumin ◽  
Urinary Albumin Excretion Rate ◽  
Albumin Excretion

Abstract Objective To explore the changes of proopiomelanocortin (POMC) and Agouti-Related Peptide (AgRP) expression in brain and kidney tissues under insulin intervention at different stages of diabetic nephropathy (DN) rats. Methods The male Sprague-Dawley (SD) rats of DN were treated with high-fat diet for 8 weeks and induced by intraperitoneally injection of streptozotocin (30 mg/kg) for one time. Then DN rats were also injected insulin subcutaneously at 2–5 U/(kg·24 h) from initiation of the streptozotocin. Kidney tissue, blood sample, and 24 h-urine were collected to detect the ratio of kidney/body weight, blood glucose and 24-h urinary albumin excretion rate at different stages (4, 8, 12, and 16 weeks). Immunohistochemistry assay was used to measure the expression of POMC and AgRP at different stages of DN rats. Results The DN rats were established successfully. With the progression of DN, blood glucose, 24-h urinary albumin excretion rate and kidney body weight ratio increased significantly, while decreased when insulin was injected. Immunohistochemistry showed that the expression levels of POMC were decreased gradually in brain and kidney tissues. Conversely, the expression of AgRP in kidney was highest at week 8 and then decreased gradually. The effect of insulin on normalizing POMC and AgRP expression in brain and renal tissues was also observed in DKD rats. Conclusion With the progression of DN, the expression of POMC and AgRP in kidney tissues was observed at different stages of disease, and their expressions were significantly normalized by insulin. The mechanism of in situ expression of POMC and AGRP in kidney to the progression of DN needs further investigations.

Glycosaminoglycans as a Possible Tool for Micro- and Macroalbuminuria in Diabetic Patients. A Pilot Study

1997 ◽  
Vol 25 (2) ◽  
pp. 81-86 ◽  
Author(s):  
G Sorrenti ◽  
M Grimaldi ◽  
N Canova ◽  
E Palazzini ◽  
N melchionda
Keyword(s):  
Type Ii Diabetes ◽  
Excretion Rate ◽  
Albumin Excretion Rate ◽  
Favourable Effect ◽  
Diabetic Patients ◽  
Type Ii ◽  
Therapeutic Tool ◽  
Albumin Excretion ◽  
End Of Treatment

The aim was to investigate sulodexide as a possible therapeutic tool for treating micro- and macroalbuminuria in diabetic patients. Fifteen patients (13 micro- and 2 macroalbuminuric) with Type II diabetes, were treated with 600 lipoprotein-lipase releasing units of sulodexide by the intramuscular route, daily for 28 days, and followed up for 2 months. The main evaluation parameter was the albumin excretion rate. At the end of treatment, six of the 13 microalbuminuric patients showed a decrease in the albumin excretion rate, which increased again in three of the six during follow-up. In the two macroalbuminuric patients the albumin excretion rate decreased at the end of treatment and remained unchanged after a further 2 months. Overall analysis (15 patients) showed a significant decrease ( P < 0.05) in the albumin excretion rate compared with baseline. Metabolic control and blood pressure remained unchanged during the entire period of study. No adverse events were registered. It is concluded that sulodexide administration has a favourable effect in reducing the albumin excretion rate in Type II diabetic patients with micro- and macroalbuminuria.

scholarly journals P11.39 Chloroquine as an anti-glioblastoma therapeutic: repurposing of an old drug

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii51-iii52
Author(s):  
L Roy ◽  
M Poirier ◽  
D Fortin
Keyword(s):  
Median Survival ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Plasma Concentrations ◽  
Progression Free Survival ◽  
Fold Increase ◽  
Wistar Rat ◽  
Control Group ◽  
Primary Brain Tumour

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive type of primary brain tumour in adults. These tumours depict anarchic proliferation and brain infiltration as well as radio- and chemoresistant profiles. The complete surgical resection is unachievable and responses to standard therapy are transitory. Recurrence is thus inevitable and patient prognosis is generally less than 15 months. Transforming growth factor-beta (TGF-β) holds a substantial role in supporting the GBM phenotype. We showed that TGF-β 1 expression levels correlate with overall and progression-free survival in newly diagnosed GBM patient. We also observed that chloroquine (CQ) can reduce the production of TGF-β together with proliferation, invasion, radioresistance and radio-induced invasion in vitro. Unfortunately, little is known regarding the ability of CQ to penetrate the blood-brain barrier (BBB). Therefore, our objective is to determine whether intravenous (IV) or intra-arterial (IA) infusions of CQ and hydroxychloroquine (HCQ), a pharmacological analog of CQ, can yield therapeutic brain concentrations. MATERIAL AND METHODS To assess BBB penetration, the brain, plasma and cerebrospinal fluid (CSF) concentrations of CQ/HCQ were measured by LCMS/MS at different timepoints post-IV or post-IA infusions with 20 mg/kg of CQ/HCQ in tumour-free Wistar rat. For the survival studies, We implanted 10’000 F98 murin glioblastoma cells in the right putamen of Fischer rats. Ten days post-implantation, IA and IV infusion were accomplished through cannulations of the external right carotid and tail vein respectively. RESULTS With IV injections, CQ/HCQ brain concentrations 15 minutes post-injection reached 15.76 mg/g (0.18 µM) and 1.67 mg/g (0.078 µM) respectively. However, following IA infusions, we observed a 1.74 and 20.9 fold increase (20 mg/kg HCQ) as well as 7.1 and 84.7-fold-increase (20 mg/kg CQ) in contra- and ipsilateral brain concentrations respectively. Although brain concentrations gradually decreased over time post-IA infusions, the ipsilateral hemisphere CQ concentration was still 82.81 mg/g (34.52 µM) after 6 hours. Whereas plasma concentrations were very similar following IV and IA infusions, both molecules barely accumulated in the CSF and only when using IA infusions. The median survival of the control group (IA phosphate-buffered saline) and the group treated with 20 mg/kg CQ IV were 23.5 days and 24.5 days respectively. However, rats injected with 20 mg/kg CQ IA had a median survival of 28.5 days. CONCLUSION These results suggest that IA CQ could be used to abrogate the GBM phenotype. As TGF-β is associated with resistance to both radio- and chemotherapy, we plan to characterize the combination of IA infusions of CQ in combination with radiation or chemotherapy (carboplatin).

scholarly journals Protective Effects of Unsaponifiable Matter from Perilla Seed Meal on UVB-induced Damages and the Underlying Mechanisms in Human Skin Fibroblasts

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 644 ◽  
Author(s):  
Hana Lee ◽  
Jeehye Sung ◽  
Younghwa Kim ◽  
Heon Sang Jeong ◽  
Junsoo Lee
Keyword(s):  
Unsaponifiable Matter ◽  
Transforming Growth Factor Beta ◽  
Collagen Synthesis ◽  
Transforming Growth Factor ◽  
Skin Aging ◽  
Seed Meal ◽  
Activator Protein 1 ◽  
Protective Effects ◽  
Uvb Exposure ◽  
Perilla Seed

Unsaponifiable matter (USM) from perilla seed meal contains numerous phytochemicals, including tocopherols, phytosterols, squalene, and policosanols, that exhibit antioxidant and health-promoting properties. In this study, the protective effects of USM on UVB-induced skin aging were investigated in Hs68 cells. UVB irradiation decreased cell viability by 26% compared to the control. However, USM blocked UVB-induced cytotoxicity. Moreover, USM treatment significantly decreased the UVB-induced production of reactive oxygen species and attenuated the UVB-induced production and mRNA expression of matrix metalloproteinases (MMPs) by inhibiting the phosphorylation of mitogen-activated protein kinases and activator protein 1 (AP-1). Furthermore, UVB exposure led to a 49.4% reduction in collagen synthesis. However, USM treatment restored collagen synthesis through upregulation of the transforming growth factor beta (TGF-β)/Smad2/3 pathways. These data indicate that USM regulates the production of MMPs and collagen by modulation of the TGF-β/Smad pathway and AP-1 activity, suggesting that USM may be a useful anti-photoaging ingredient.

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