Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension1

Cheng, Hao; Wang, Connie J.; Moeckel, Gilbert; Zhang, Mingzhi; McKanna, James A.; Harris, Raymond C.

doi:10.1046/j.1523-1755.2002.00520.x

Cited by 184 publications

(190 citation statements)

References 65 publications

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“…Therefore, Celecoxib is not simply blocking the effect of COX-2, but is also perturbing COX-2 protein production; a finding noted in previous studies (Cheng et al, 2002;Agarwal et al, 2003). In COX-2 expressing HT29 colon cancer cell lines, COX-2 inhibition with another selective COX-2 inhibitor SC236 (a structural analogue of Celecoxib) showed that at high levels of inhibitor (concentrations greater than 75 mm), COX-2 enzyme activity was completely inactivated.…”

Section: Celecoxib Decreases Cox-2 Protein Expressionmentioning

confidence: 68%

Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer

et al. 2007

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Cyclooxygenase-2 (COX-2) is associated with poor-prognosis breast cancer. We used a nude mouse xenograft model to determine the effects of COX-2 inhibition in breast cancer. Oestrogen receptor (ER)-positive MCF7/HER2-18 and ER-negative MDAMB231 breast cancer cell lines were injected into nude mice and allowed to form tumours. Mice then received either chow containing Celecoxib (a COX-2 inhibitor) or control and tumour growth measured. Tumour proliferation, apoptosis, COX-2, lymphangiogenesis and angiogenesis were assessed by immunohistochemistry (IHC), Western blotting or Q-PCR. Celecoxib inhibited median tumour growth in MCF7/HER2-18 (58.7%, P ¼ 0.029) and MDAMB231 (46.3%, P ¼ 0.0002) cell lines compared to control. Cyclooxygenase-2 expression decreased following Celecoxib treatment (MCF7/HER2-18 median control 65.3% vs treated 22.5%, P ¼ 0.0001). Celecoxib increased apoptosis in MCF7/HER2-18 tumours (TUNEL 0.52% control vs 0.73% treated, P ¼ 0.0004) via inactivation of AKT (median pAKT ser473 57.3% control vs 35.5% treated, P ¼ 0.0001 -confirmed at Western blotting). Q-PCR demonstrated decreased podoplanin RNA (lymphangiogenesis marker) in the MCF7/HER2-18 -median 2.9 copies treated vs 66.6 control (P ¼ 0.05) and MDAMB231-treated groups -median 160.7 copies vs 0.05 control copies (P ¼ 0.015), confirmed at IHC. Cyclooxygenase-2 is associated with high levels of activated AKT ser473 and lymphangiogenesis in breast cancer. Cyclooxygenase-2 inhibition decreases tumour growth, and may potentially decrease recurrence, by inactivating AKT and decreasing lymphangiogenesis.

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Section: Celecoxib Decreases Cox-2 Protein Expressionmentioning

confidence: 68%

Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer

et al. 2007

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“…COX metabolites have been implicated in the renal damage that occurs in animal models and patients with metabolic syndrome [58][59][60][61][62]. There are at least two COX enzymes, COX-1 and COX-2, expressed in the kidney.…”

Section: Eicosanoids As a Therapeutic Target For Renal Damage In Cardmentioning

confidence: 99%

“…There are at least two COX enzymes, COX-1 and COX-2, expressed in the kidney. COX metabolites play a critical role in renal blood flow regulation, renin generation and vascular inflammation [25,58,63]. Alterations in COX metabolites contribute to endothelial dysfunction and renal damage in diabetes [56,64,65].…”

Section: Eicosanoids As a Therapeutic Target For Renal Damage In Cardmentioning

confidence: 99%

“…Prostaglandin I2 (PGI2) can oppose the deleterious TXA2 effects associated with chronic kidney disease [61]. A number of studies have linked obesity and type 2 diabetes to increased generation of COX-2 metabolites in the kidney [29,58,60]. A consistent finding in these studies has been a decreased PGI2/TXA2 ratio in diabetic patients and animal models of diabetes [62,67].…”

Section: Eicosanoids As a Therapeutic Target For Renal Damage In Cardmentioning

confidence: 99%

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Eicosanoids and renal damage in cardiometabolic syndrome

Imig

2008

Expert Opinion on Drug Metabolism & Toxicology

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Obesity, hypertension and type 2 diabetes are major contributing factors to the increase in the number of patients that have chronic kidney disease. The clustering of visceral obesity and cardiovascular risk factors has been designated metabolic syndrome or cardiometabolic syndrome. Cardiometabolic syndrome is associated with a complex systemic inflammatory state that has been implicated in medically important complications including endothelial dysfunction. Inflammation, endothelial dysfunction, and insulin resistance are interrelated and have reciprocal relationships that link cardiovascular and metabolic diseases. Ultimately, cardiometabolic syndrome increases the risk for cardiovascular events and end organ damage. Although the number of patients with cardiometabolic syndrome is escalating, therapeutic approaches have not been developed that provide protection to the kidney. Eicosanoids are altered in cardiometabolic syndrome and contribute the progression of renal injury. The anti-hypertensive and anti-inflammatory actions of epoxides and soluble epoxide hydrolase inhibitors make these attractive eicosanoid therapeutic targets for chronic kidney disease in patients with cardiometabolic syndrome. Keywordskidney; epoxyeicosatrienoic acids; epoxide hydrolase; obesity; cytokines; inflammation Cardiometabolic SyndromeIn recent years, the number of obese people in the world is growing rapidly and has reached epidemic status. Obesity is the central phenotype in metabolic syndrome, also known as cardiometabolic syndrome that clusters with other cardiovascular risk factors. These other cardiovascular risk factors include hypertension, type 2 diabetes, insulin resistance, low high-density lipoproteins (HDL) cholesterol, elevated triglycerides, microalbuminuria, and atherosclerosis [1,2,3] (Figure 1). The Adult treatment Panel II of the National Cholesterol Education Program has defined metabolic syndrome as any three of the following five traits: visceral obesity, hypertension, hypertriglyceridemia, low HDL cholesterol, and impaired fasting glucose [4]. Although obesity is the phenotypic hallmark of cardiometabolic syndrome, the other risk factors that manifest in individuals varies greatly. Blood pressure elevation in obese individuals is closely related to weight gain; however, not all obese individuals become hypertensive [5][6][7][8]. The relationship between obesity and hypertension is well established but the exact consequences to end organ damage remains unknown. Interestingly, hypertension and diabetes account for seventy percent of patients with end stage renal disease (ESRD) and the number of patients with ESRD will double in this decade [9,10]. One of the main reasons for the doubling in ESRD patients is the increase in obesity related type 2 diabetes and its co-existence with hypertension.

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“…Cheng et al 33 showed that p38 in macula densa cells is involved in regulation of cyclooxygenase-2 (COX-2) under certain conditions, such as low chloride tubular content. Since COX-2-derived metabolites have been implicated in the pathophysiology of progressive renal disease, including diabetes, 34,35 this is an attractive pathway that may link p38 with the development of nephropathy in diabetes. Interestingly, p38 localization in diabetic rats was almost identical to that of COX-2, as observed in our previous studies.…”

Section: Renal P38 In Experimental Diabetesmentioning

confidence: 99%

Renal p38 MAP kinase activity in experimental diabetes

Komers

Lindsley

Oyama

et al. 2007

Laboratory Investigation

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Renal cell activity of p38 mitogen-activated protein kinase (p38) is increased in the diabetic milieu. p38 mediates signals relevant for the development of diabetic nephropathy (DN). However, renal p38 in Type 1 diabetes in vivo, particularly in conditions reflecting the differences in metabolic control, and its activity in advanced stages of DN, has received less attention. We examined the p38 pathway in renal cortex of rats with streptozotocin diabetes (4 weeks) with poor (DS), moderate (DM), and intensive (DII) metabolic control, achieved by varying doses of insulin therapy. Renal p38 was also studied in 12-month diabetic rats with established nephropathy (DM12) and compared with age-matched controls. p38 activity (in vitro kinase assay and expression of phosphorylated (active) p38 (P-p38)) was increased in DM and DS rats, as compared with non-diabetic controls, and attenuated by intensive insulin treatment. In all groups, P-p38 was predominantly localized in macula densa cells. Diabetic rats also demonstrated P-p38 immunoreactivity in the distal tubule and glomeruli. Enhanced p38 activity in DS and DM rats was not associated with increases in expression of active mitogen-activated protein kinase 3/6, an activator of p38, but paralleled with increased expression of scaffolding protein transforming growth factor-b-activated protein kinase 1-binding protein 1. Expression of mitogen-activated protein phosphatase-1 (MKP-1), one of the phosphatases involved in inactivation of mitogen-activated protein kinase signaling, was increased in all diabetic groups, irrespective of metabolic control. Renal p38 activation was also detectable in D12 rats with established albuminuria and glomerulosclerosis. In summary, renal cortical p38 activity was increased in diabetic rats at early and advanced stages of nephropathy, as compared with non-diabetic animals, and attenuated by improved metabolic control. p38 activation in diabetes is likely to occur via multiple pathways and cannot be explained by downregulation of MKP-1. KEYWORDS: diabetic nephropathy; hyperglycemia; p38 mitogen-activated protein kinase; proteinuria; signaling High glucose concentrations, and potentially other factors in the diabetic milieu, trigger pathophysiological signals mediated by the activation of specific kinase cascades. Altered activation of mitogen-activated protein (MAP) kinases (MAPK) occurs under these conditions and results in a broad spectrum of acute and long-term effects including mobilization of intracellular calcium and induction of gene expression. 1 In the kidney, such aberrant activation of MAPK cascades may perturb the balance of humoral and cytokine systems responsible for regulating vascular tone, permeability, renal cellular growth, and composition of the extracellular/mesangial matrix (ie, factors associated with the development of diabetic nephropathy). 2,3 p38 mitogen-activated protein kinase (p38), a member of the MAPK family, is activated by a number of stimuli. As a stress-activated kinase, p38 is activated by physical and ch...

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Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension1

Abstract: These results suggest that in an experimental model of diabetes and hypertension, inhibition of COX-2 expression decreases potential mediators of glomerular and tubulointerstitial injury and also decreases biochemical, functional and structural markers of renal injury.

Cited by 184 publications

References 65 publications

Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer

Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer

Eicosanoids and renal damage in cardiometabolic syndrome

Renal p38 MAP kinase activity in experimental diabetes

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