scholarly journals COX-2-derived prostaglandins as mediators of the deleterious effects of nicotine in chronic kidney disease

2020 ◽  
Vol 318 (2) ◽  
pp. F475-F485 ◽  
Author(s):  
S. Rangarajan ◽  
G. Rezonzew ◽  
P. Chumley ◽  
H. Fatima ◽  
M. Y. Golovko ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Injury ◽  
Tap Water ◽  
Osmotic Minipump ◽  
Renal Ablation ◽  
Cox 2

Tobacco smoking has been identified as a risk factor in the progression of chronic kidney disease (CKD). In previous studies, we showed that nicotine induces cyclooxygenase (COX)-2 expression in vivo and in vitro and that the administration of nicotine in vivo worsens the severity of renal injury in a model of subtotal renal ablation. In the present study, we tested the role of COX-2-derived prostaglandins on the deleterious effects of nicotine in CKD. Sham and 5/6 nephrectomy (5/6Nx) rats received tap water or nicotine (100 μg/mL) in the drinking water for 12 wk. Additional groups also systemically received the COX-2 inhibitor NS-398 (1.5 mg·kg−1·day−1 via osmotic minipump). The administration of nicotine worsened renal injury and proteinuria in 5/6Nx rats and increased proteinuria in sham rats. 5/6Nx rats had increased cortical production of the prostaglandins PGE2, PGI2, PGD2, and PGF2α and of thromboxane A2. In these rats, nicotine reduced the production of all prostaglandins examined except thromboxane A2. Treatment with the COX-2 inhibitor NS-398 resulted in complete inhibition of all prostaglandins studied and ameliorated renal injury and proteinuria in 5/6Nx rats on nicotine but not in 5/6 Nx rats on tap water. Nicotine also reduced the expression of megalin in all groups examined, and this was partially prevented by COX-2 inhibition. In the present study, we showed that in CKD, nicotine worsens renal injury at least in part by producing an imbalance in the production of prostaglandins. This imbalance in the production of prostaglandins likely plays a role in the deleterious effects of smoking on the progression of CKD.

scholarly journals AIM2 Inflammasome Contributes to Aldosterone-induced Renal Injury via Endoplasmic Reticulum Stress

2021 ◽  
Author(s):  
Yong Wu ◽  
Huan Yang ◽  
Sujuan Xu ◽  
Ming Cheng ◽  
Jie Gu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Endoplasmic Reticulum Stress ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Inflammasome Activation ◽  
Mineralocorticoid Receptor Antagonist

Inflammatory response and renal fibrosis are the hallmarks of chronic kidney disease (CKD). However, the specific mechanism of aldosterone-induced renal injury in the progress of CKD requires elucidation. Emerging evidence has demonstrated that absent in melanoma 2 (AIM2)-mediated inflammasome activation and endoplasmic reticulum stress (ERS) play a pivotal role in the renal fibrosis. Here, we investigated whether overexpression or deficiency of AIM2 affects ERS and fibrosis in aldosterone-infused renal injury. Interestingly, we found that AIM2 was markedly expressed in the diseased proximal tubules from human and experimental chronic kidney disease. Mechanically, overactivation of AIM2 aggravated aldosterone-induced ERS and fibrotic changes in vitro while knockdown of AIM2 blunted these effects in vivo and vitro. By contrast, AIM2 deficiency ameliorated renal structure and function deterioration, decreased proteinuria levels and lower systolic blood pressure in vivo; silencing of AIM2 blocked inflammasome-mediated signaling pathway, relieved ERS and fibrotic changes in vivo. Furthermore, mineralocorticoid receptor antagonist eplerenone and ERS inhibitor tauroursodeoxycholic acid (TUDCA) had nephroprotective effects on the basis of AIM2 overactivation in vitro while they failed to produce a more remarkable reno-protective effect on the treatment of AIM2 silence in vitro. Notably, the combination of TUDCA with AIM2 knockdown significantly reduced proteinuria levels in vivo. Additionally, immunofluorescence assay identified that apoptosis-associated speck-like protein (ASC) recruitment and Gasdermin-D (GSDMD) cleavage respectively occurred in the glomeruli and tubules in vivo. These findings establish a crucial role for AIM2 inflammasome in aldosterone-induced renal injury, which may provide a novel therapeutic target for the pathogenesis of CKD.

Effects and Mechanism of Combination of Rhein and Danshensu in the Treatment of Chronic Kidney Disease

2015 ◽  
Vol 43 (07) ◽  
pp. 1381-1400 ◽  
Author(s):  
Yue Guan ◽  
Xiao-Xiao Wu ◽  
Jia-Lin Duan ◽  
Ying Yin ◽  
Chao Guo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Injury ◽  
Salvia Miltiorrhiza ◽  
Underlying Mechanism ◽  
Clinical Practices ◽  
Disease Treatment ◽  
First Time

Traditional Chinese medicine (TCM) plays a systemic role in disease treatment, targeting multiple etiological factors simultaneously. Based on clinical experience, rhubarb and Salvia miltiorrhiza are commonly prescribed together for the treatment of chronic kidney disease (CKD) and have been proven to be very effective. However, the rationale of the combination remains unclear. The major active ingredients of these two herbs are rhein (RH) and danshensu (DSS), respectively. The aim of this paper is to investigate the renoprotective effects of RH and DSS in vitro and in vivo, and the underlying mechanism. A total of 5/6 nephrectomy rats and HK-2 cells were subjected to chronic renal injury. The combination of RH and DSS conferred a protective effect, as shown by a significant improvement in the renal function, blood supply, and fibrotic degree. Proinflammatory cytokines and adhesion molecules were suppressed by RH and DSS through NK-[Formula: see text]B signaling. The combination also inhibited apoptosis by up-regulating Bcl-2 and down-regulating Bax. Inhibiting the TGF-[Formula: see text]/Smad3 pathway was at least in part involved in the antifibrotic mechanism of the combination treatment of RH and DSS. This study demonstrates for the first time the renoprotective effect and the mechanism of RH and DSS combination on chronic renal injury. It could provide experimental evidence to support the rationality of the combinatorial use of TCM in clinical practices.

scholarly journals The Role of Propolis in Pulp Pain by Inhibiting Cyclooxygenase-2 Expression

2021 ◽  
Vol 11 (1) ◽  
pp. 11
Author(s):  
Ira Widjiastuti ◽  
Widya Saraswati ◽  
Annisa Rahma
Keyword(s):  
Side Effects ◽  
Pain Relief ◽  
Inflammatory Pain ◽  
Cyclooxygenase 2 ◽  
Propolis Extract ◽  
In Silico Studies ◽  
Cox 2

Background: Inflammation of the pulp can lead to elicit pain. Pain in inflammation is induced by the cyclooxygenase-2 enzyme (COX-2) which induces prostaglandin E2 (PGE2) resulting in pain. Pain in the pulp can be relieved by eugenol. In its application, eugenol is toxic to pulp fibroblasts. Due to the side effect, it is worth considering other biocompatible materials with minimal side effects, such as propolis. Flavonoids and phenolic acids that contained in propolis can inhibit COX-2. Therefore, an analysis outlined in the literature review is needed to examine the results of research related to the role of propolis as pulp pain relief by inhibiting COX-2 expression. Purpose: To analyze the role of propolis in pulp pain by inhibiting COX-2 expression. Reviews: Propolis extract that extracted by ethanol, water, and hydroalcohol has pain relief properties in the pulp by inhibiting COX-2 by directly binding to the COX-2 receptors and by reducing the production of proinflammatory cytokines which are COX-2 inducers, proven through in vivo, in vitro, and in silico studies in various target cell organs. Conclusion: Propolis extract has high prospect as inflammatory pain inhibitor in the pulp by inhibit COX-2 expression.

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.

Coordinate expression of secretory phospholipase A2 and cyclooxygenase-2 in activated human keratinocytes

2000 ◽  
Vol 278 (4) ◽  
pp. C822-C833 ◽  
Author(s):  
Krystyna E. Rys-Sikora ◽  
Raymond L. Konger ◽  
John W. Schoggins ◽  
Rama Malaviya ◽  
Alice P. Pentland
Keyword(s):  
Wound Repair ◽  
Human Keratinocytes ◽  
Plating Density ◽  
Coordinate Expression ◽  
Cox 2 ◽  
Type V ◽  
In Vitro Wounding

PGE2 levels are altered in human epidermis after in vivo wounding; however, mechanisms modulating PGE2 production in activated keratinocytes are unclear. In previous studies, we showed that PGE2 is a growth-promoting autacoid in human primary keratinocyte cultures, and its production is modulated by plating density, suggesting that regulated PGE2 synthesis is an important component of wound healing. Here, we examine the role of phospholipase A2(PLA2) and cyclooxygenase (COX) enzymes in modulation of PGE2 production. We report that the increased PGE2 production that occurs in keratinocytes grown in nonconfluent conditions is also observed after in vitro wounding, indicating that similar mechanisms are involved. This increase was associated with coordinate upregulation of both COX-2 and secretory PLA2 (sPLA2) proteins. Increased sPLA2 activity was also observed. By RT-PCR, we identified the presence of type IIA and type V sPLA2, along with the M-type sPLA2 receptor. Thus the coordinate expression of sPLA2 and COX-2 may be responsible for the increased prostaglandin synthesis in activated keratinocytes during wound repair.

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 The Ser/Thr kinase p90RSK promotes kidney fibrosis by modulating fibroblast–epithelial crosstalk

2019 ◽  
Vol 294 (25) ◽  
pp. 9901-9910 ◽  
Author(s):  
Ling Lin ◽  
Chaowen Shi ◽  
Zhaorui Sun ◽  
Nhat-Tu Le ◽  
Jun-Ichi Abe ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Nuclear Translocation ◽  
Disease Model ◽  
Kidney Fibrosis ◽  
Cellular Processes ◽  
Ribosomal Protein S6 ◽  
Forkhead Box

Healthy kidney structure and environment rely on epithelial integrity and interactions between epithelial cells and other kidney cells. The Ser/Thr kinase 90 kDa ribosomal protein S6 kinase 1 (p90RSK) belongs to a protein family that regulates many cellular processes, including cell motility and survival. p90RSK is predominantly expressed in the kidney, but its possible role in chronic kidney disease (CKD) remains largely unknown. Here, we found that p90RSK expression is dramatically activated in a classic mouse obstructive chronic kidney disease model, largely in the interstitial FSP-1–positive fibroblasts. We generated FSP-1–specific p90RSK transgenic mouse (RSK-Tg) and discovered that these mice, after obstructive injury, display significantly increased fibrosis and enhanced tubular epithelial damage compared with their wt littermates (RSK-wt), indicating a role of p90RSK in fibroblast–epithelial communication. We established an in vitro fibroblast–epithelial coculture system with primary kidney fibroblasts from RSK-Tg and RSK-wt mice and found that RSK-Tg fibroblasts consistently produce excessive H2O2 causing epithelial oxidative stress and inducing nuclear translocation of the signaling protein β-catenin. Epithelial accumulation of β-catenin, in turn, promoted epithelial apoptosis by activating the transcription factor forkhead box class O1 (FOXO1). Of note, blockade of reactive oxygen species (ROS) or β-catenin or FOXO1 activity abolished fibroblast p90RSK-mediated epithelial apoptosis. These results make it clear that p90RSK promotes kidney fibrosis by inducing fibroblast-mediated epithelial apoptosis through ROS-mediated activation of β-catenin/FOXO1 signaling pathway.

AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease

2012 ◽  
Vol 303 (7) ◽  
pp. F1037-F1048 ◽  
Author(s):  
Christoph Fraune ◽  
Sascha Lange ◽  
Christian Krebs ◽  
Alexandra Hölzel ◽  
Jana Baucke ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Injury ◽  
Plasma Concentrations ◽  
Renin Angiotensin System ◽  
Pivotal Role ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Renin Inhibition

The role of the renin-angiotensin system in chronic kidney disease involves multiple peptides and receptors. Exerting antipodal pathophysiological mechanisms, renin inhibition and AT1 antagonism ameliorate renal damage. However, it is unclear which mechanism exerts better nephroprotection. We compared the renin inhibitor aliskiren with the AT1 antagonist losartan in mice with chronic kidney disease due to renal ablation. Doses were adjusted to equipotent inhibition of the renin-angiotensin system, determined via a dose-response quantifying plasma and renal renin expression. Six-week treatment with either 500 mg/l drinking water losartan or 50 mg·kg−1·day−1 aliskiren significantly decreased albuminuria, glomerular damage, and transcription rates of renal injury markers to a similar extent. An array analysis comparing renal gene expression of losartan- and aliskiren-treated mice evaluating >34,000 transcripts demonstrated regulation for 14 genes only, with small differences. No superior nephroprotection was found by combining losartan and aliskiren. Compared with plasma concentrations, aliskiren accumulated ∼7- to 29-fold in the heart, liver, lung, and spleen and ∼156-fold in the kidney. After withdrawal, plasma concentrations dropped to zero within 24 h, whereas renal tissue concentrations declined slowly over days. Withdrawal of aliskiren in mice with chronic kidney disease revealed a significantly delayed re-increase in albuminuria compared with withdrawal of losartan. This study demonstrates equieffective nephroprotection of renin inhibition and AT1 antagonism in mice with chronic kidney disease without additional benefit of combination therapy. These observations underscore the pivotal role of targeting ANG II to reduce renal injury.

scholarly journals COX-2 mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla

2014 ◽  
Vol 307 (1) ◽  
pp. F25-F32 ◽  
Author(s):  
Fei Wang ◽  
Xiaohan Lu ◽  
Kexin Peng ◽  
Li Zhou ◽  
Chunling Li ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Expression ◽  
Renal Medulla ◽  
Receptor Expression ◽  
Ang Ii ◽  
Cox 2 ◽  
Renin Content

(Pro)renin receptor (PRR) is predominantly expressed in the distal nephron where it is activated by angiotensin II (ANG II), resulting in increased renin activity in the renal medulla thereby amplifying the de novo generation and action of local ANG II. The goal of the present study was to test the role of cycloxygenase-2 (COX-2) in meditating ANG II-induced PRR expression in the renal medulla in vitro and in vivo. Exposure of primary rat inner medullary collecting duct cells to ANG II induced sequential increases in COX-2 and PRR protein expression. When the cells were pretreated with a COX-2 inhibitor NS-398, ANG II-induced upregulation of PRR protein expression was almost completely abolished, in parallel with the changes in medium active renin content. The inhibitory effect of NS-398 on the PRR expression was reversed by adding exogenous PGE2. A 14-day ANG II infusion elevated renal medullary PRR expression and active and total renin content in parallel with increased urinary renin, all of which were remarkably suppressed by the COX-2 inhibitor celecoxib. In contrast, plasma and renal cortical active and total renin content were suppressed by ANG II treatment, an effect that was unaffected by COX-2 inhibition. Systolic blood pressure was elevated with ANG II infusion, which was attenuated by the COX-2 inhibition. Overall, the results obtained from in vitro and in vivo studies established a crucial role of COX-2 in mediating upregulation of renal medullary PRR expression and renin content during ANG II hypertension.

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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