scholarly journals The In Vivo Effects of Adenine-Induced Chronic Kidney Disease on Some Renal and Hepatic Function and CYP450 Metabolizing Enzymes

2017 ◽  
pp. 263-271 ◽  
Author(s):  
M. AL ZA’ABI ◽  
A. SHALABY ◽  
P. MANOJ ◽  
B. H. ALI
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Hepatic Function ◽  
Moderate Degree ◽  
Metabolizing Enzymes ◽  
Sleeping Time ◽  
Plasma Enzymes ◽  
Plasma Theophylline ◽  
Pentobarbitone Sleeping Time

Adenine-induced model of chronic kidney disease (CKD) is a widely used model especially in studies testing novel nephroprotective agents. We investigated the effects of adenine-induced CKD in rats on the activities of some xenobiotic metabolizing enzymes in liver and kidneys, and on some in vivo indicators of drug metabolism (viz pentobarbitone sleeping time, and plasma concentration of theophylline 90 min post administration). CKD was induced by orally feeding adenine (0.25 % w/w) for 35 days. Adenine induced all the characteristics of CKD, which was confirmed by biochemical and histological findings. Glutathione concentration and activities of some enzymes involved in its metabolism were reduced in kidneys and livers of rats with CKD. Renal CYP450 1A1 activity was significantly inhibited by adenine, but other measured isoenzymes (1A2, 3A4 and 2E1) were not significantly affected. Adenine significantly prolonged pentobarbitone-sleeping time and increased plasma theophylline concentration 90 min post administration. Adenine also induced a moderate degree of hepatic damages as indicated histologically and by significant elevations in some plasma enzymes. The results suggest that adenine-induced CKD is associated with significant in vivo inhibitory activities on some drug-metabolizing enzymes, with most of the effect on the kidneys rather than the liver.

scholarly journals In vivo renal arginine release is impaired throughout development of chronic kidney disease

2010 ◽  
Vol 298 (1) ◽  
pp. F95-F102 ◽  
Author(s):  
Gin-Fu Chen ◽  
Chris Baylis
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Plasma Flow ◽  
Severe Injury ◽  
Normal Kidney ◽  
Plasma Citrulline ◽  
Renal Ablation ◽  
Early Injury ◽  
Production Increase

The kidney is a major site of arginine synthesis where citrulline is converted to arginine via argininosuccinate synthase (ASS) and lyase (ASL). The rate-limiting step in arginine synthesis by the normal kidney is the rate of citrulline delivery and uptake to the renal cortex. We tested whether with chronic kidney disease (CKD) renal arginine synthesis may be compromised. Using the renal ablation/infarction (A/I) injury model, we measured renal citrulline delivery and uptake as well as arginine release at early, moderate, and severe stages of CKD vs. healthy controls. The renal plasma flow (RPF) and arterial-renal venous difference was measured at baseline and during citrulline infusion. Citrulline delivery was reduced at all stages of disease due to marked reductions in RPF and despite moderately increased plasma citrulline. Early after A/I, the kidney demonstrated a compensatory increase in citrulline uptake while at moderate and severe injury baseline citrulline uptake fell. At all stages of CKD, renal arginine release was markedly reduced. Citrulline infusion increased plasma citrulline in all groups, resulting in increased renal delivery vs. baseline. In healthy kidneys and early injury, citrulline uptake increased with the infusion, but only in the normal kidney did arginine production increase in parallel with the increased citrulline uptake. At moderate and severe injury, there was no increase in citrulline uptake or arginine production. The fall in arginine production in A/I was due to an early loss of ASS and ASL conversion of citrulline, which combined with a later reduction in citrulline uptake.

scholarly journals A Pilot Study of a Natural Food Supplement as New Possible Therapeutic Approach in Chronic Kidney Disease Patients

2020 ◽  
Vol 13 (7) ◽  
pp. 148 ◽  
Author(s):  
Annalisa Noce ◽  
Alessio Bocedi ◽  
Margherita Campo ◽  
Giulia Marrone ◽  
Manuela Di Lauro ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
High Performance ◽  
Glutathione Transferase ◽  
Food Supplement ◽  
Array Detector ◽  
Natural Food ◽  
Inflammatory Status

The identification of natural bioactive compounds, able to counteract the abnormal increase of oxidative stress and inflammatory status in chronic degenerative non-communicable diseases is useful for the clinical management of these conditions. We tested an oral food supplement (OFS), chemically characterized and evaluated for in vitro and in vivo activity. Vitamin C, analyzed by High Performance Liquid Chromatography-Diode Array Detector (HPLC-DAD), was 0.19 mg/g in rosehip dry extract and 15.74 mg/capsule in the OFS. The identification of polyphenols was performed by HPLC-DAD; the total antioxidant capacity was assessed by Folin–Ciocalteu test. Total polyphenols were 14.73 mg/g gallic acid equivalents (GAE) for rosehip extract and 1.93 mg/g GAE for OFS. A total of 21 chronic kidney disease (CKD) patients and 10 healthy volunteers were recruited. The evaluation of routine laboratory and inflammatory parameters, erythrocyte glutathione transferase (e-GST), human oxidized serum albumin (HSAox), and assessment of body composition were performed at two different times, at baseline and after 5 weeks of OFS assumption. In the study, we highlighted a significant decrease of traditional inflammatory biomarkers (such as C-reactive protein, erythrocyte sedimentation rate, platelet to lymphocyte ratio) and other laboratory parameters like e-GST, azotaemia, and albuminuria after OFS treatment in CKD patients. Moreover, we demonstrated a lipid profile improvement in CKD patients after OFS supplementation.

scholarly journals 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

2017 ◽  
Vol 234 (1) ◽  
pp. T125-T140 ◽  
Author(s):  
Peter Kolkhof ◽  
Lars Bärfacker
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Clinical Trials ◽  
Kidney Disease ◽  
Research And Development ◽  
Mineralocorticoid Receptor ◽  
Clinical Use ◽  
Patients With Heart Failure ◽  
History Of

The cDNA of the mineralocorticoid receptor (MR) was cloned 30 years ago, in 1987. At that time, spirolactone, the first generation of synthetic steroid-based MR antagonists (MRAs), which was identified in preclinical in vivo models, had already been in clinical use for 30 years. Subsequent decades of research and development by Searle & Co., Ciba-Geigy, Roussel Uclaf and Schering AG toward identifying a second generation of much more specific steroidal MRAs were all based on the initial 17-spirolactone construct. The salient example is eplerenone, first described in 1987, coincidentally with the cloning of MR cDNA. Its launch on the market in 2003 paralleled intensive drug discovery programs for a new generation of non-steroidal MRAs. Now, 30 years after the cDNA cloning of MR and 60 years of clinical use of steroidal MRAs, novel non-steroidal MRAs such as apararenone, esaxerenone and finerenone are in late-stage clinical trials in patients with heart failure, chronic kidney disease (CKD), hypertension and liver disease. Finerenone has already been studied in over 2000 patients with heart failure plus chronic kidney disease and/or diabetes, and in patients with diabetic kidney disease, in five phase II clinical trials. Here, we reflect on the history of the various generations of MRAs and review characteristics of the most important steroidal and non-steroidal MRAs.

High Phosphorus Level Leads to Aortic Calcification via β-Catenin in Chronic Kidney Disease

2015 ◽  
Vol 41 (1) ◽  
pp. 28-36 ◽  
Author(s):  
Li Yao ◽  
Yi-ting Sun ◽  
Wei Sun ◽  
Tian-hua Xu ◽  
Chuang Ren ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Serum Levels ◽  
Aortic Calcification ◽  
In Vivo Model ◽  
Phosphorus Level ◽  
Abdominal Aortic Calcification ◽  
High Phosphorus ◽  
Abdominal Aortic

Aims: Vascular calcification is a risk factor for causing cardiovascular events and has a high prevalence among chronic kidney disease (CKD) patients. However, the molecular mechanism underlying this pathogenic process is still obscure. Methods: Vascular smooth muscle cells (VSMCs) were induced by a concentration of phosphorus (Pi) of 2.5 mM, and were subjected to cell calcification analyses. The effect of high Pi on the Wnt/β-catenin pathway was measured using a TOP/FOP-Flash reporter assay. The transcriptional regulation of β-catenin on PIT1 (a type III sodium-dependent phosphate cotransporter) was confirmed by promoter reporter and chromatin immunoprecipitation assays. The 5/6 nephrectomized rat was used as an in vivo model and was fed a high Pi diet to induce aortic calcification. Serum levels of phosphate, calcium, creatine, and blood urea nitrogen were measured, and abdominal aortic calcification was examined. Results: High Pi induced VSMC calcification, downregulated expression levels of VSMC markers, and upregulated levels of osteogenic markers. High Pi activated the Wnt/β-catenin pathway and β-catenin activity. β-Catenin was involved in the process of high Pi-induced VSMC calcification. Further investigation revealed that β-catenin transcriptionally regulated Pit1, a necessary player in VSMC osteogenic phenotype change and calcification. The in vivo study showed that β-catenin was involved in rat abdominal aortic calcification induced by high Pi. When knockdown expression of β-catenin in the rat model was investigated, we found that aortic calcification was reduced. Conclusion: These results suggest that β-catenin is an important player in high phosphorus level-induced aortic calcification in CKD.

scholarly journals FGF23 impairs peripheral microvascular function in renal failure

2018 ◽  
Vol 315 (5) ◽  
pp. H1414-H1424 ◽  
Author(s):  
Melissa Verkaik ◽  
Rio P. Juni ◽  
Ellen P. M. van Loon ◽  
Erik M. van Poelgeest ◽  
Rick F. J. Kwekkeboom ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Asymmetric Dimethylarginine ◽  
Ex Vivo ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth

Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD.NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23.

scholarly journals Mitochondrial Targeting of Herbal Medicine in Chronic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Qing Li ◽  
Changying Xing ◽  
Yanggang Yuan
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Herbal Medicine ◽  
Mitochondrial Function ◽  
Conventional Medicine ◽  
Treatment Options ◽  
Renal Diseases ◽  
Public Health Issue

Chronic kidney disease (CKD) is a common progressive disease that is typically characterized by the permanent loss of nephrons and an eventual decline in glomerular filtration rate. CKD increases mortality and has a significant impact on the quality of life and the economy, which is becoming a major public health issue worldwide. Since current conventional-medicine treatment options for CKD are not satisfactory, many patients seek complementary and alternative medicine treatments including Traditional Chinese Medicine. Herbal medicine is often used to relieve symptoms of renal diseases in the clinic. The kidney is abundant in the number of mitochondria, which provide enough energy for renal function and metabolism. In recent years, a vital role for mitochondrial dysfunction has been suggested in CKD. Mitochondria have become a new target for the treatment of diseases. A growing number of studies have demonstrated herbal medicine could restore mitochondrial function and alleviate renal injury both in vivo and in vitro. In this review, we sum up the therapeutic effect of herbal medicine in CKD via targeting mitochondrial function. This implies future strategies in preventing CKD.

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