Immunohistochemical and functional correlations of renal cyclooxygenase-2 in experimental diabetes

Komers, Radko; Lindsley, Jessie N.; Oyama, T; Schutzer, William E.; Reed, John; Mader, Scott L.; Anderson, Sharon

doi:10.1172/jci10228

Cited by 178 publications

(192 citation statements)

References 66 publications

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“…Given that mesangial production of PGE2 is increased by high glucose (10,17), the present study reveals the importance of the autocrine PGE2-EP1 system in high glucose-induced matrix gene activation. Among PG-generating COX enzymes, an inducible isoform COX-2 has been implicated in the glomeruli of diabetic nephropathy (30). We therefore next examined the gene expression of COX-2 in mesangial cells.…”

Section: Role Of Autocrine Pge2-ep1 In Activating Tgf-␤ Cascade In Mementioning

confidence: 99%

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

Makino¹,

Tanaka²,

Mukoyama³

et al. 2002

Journal of the American Society of Nephrology

107

100

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Abstract. Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-␤ (TGF-␤) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-␤ and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.

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Section: Role Of Autocrine Pge2-ep1 In Activating Tgf-␤ Cascade In Mementioning

confidence: 99%

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

Makino¹,

Tanaka²,

Mukoyama³

et al. 2002

Journal of the American Society of Nephrology

107

100

View full text Add to dashboard Cite

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“…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%

“…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%

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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“…The fixed kidneys were dehydrated through a graded series of ethanols, embedded in paraffin, sectioned at 4 mm thickness, and placed onto glass slides. The immunohistochemical procedure was performed as previously described 19 using primary antibodies against phospho-p38 (Cell Signaling, 1:200). In control and diabetic rats undergoing the long-term follow-up, the kidney paraffin sections were also stained with periodic acid Schiff (PAS)-stained sections for the assessment of glomerular morphology.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Interestingly, p38 localization in diabetic rats was almost identical to that of COX-2, as observed in our previous studies. 19 The link between p38 signaling and prostanoid production in VSMC and renal cells has been well established in vitro. 11,36 Several reports have suggested that the time factor may be important in assessing the role of p38 in diabetic renal pathophysiology.…”

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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Immunohistochemical and functional correlations of renal cyclooxygenase-2 in experimental diabetes

Cited by 178 publications

References 66 publications

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

Prevention of Diabetic Nephropathy in Rats by Prostaglandin E Receptor EP1-Selective Antagonist

Eicosanoids and renal damage in cardiometabolic syndrome

Renal p38 MAP kinase activity in experimental diabetes

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