Eicosanoid regulation of the renal vasculature

Imig, John D.

doi:10.1152/ajprenal.2000.279.6.f965

Cited by 169 publications

(246 citation statements)

References 167 publications

(304 reference statements)

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“…This is evidence that PGE 2 is one COX metabolite released after EGF stimulation in OK cells. As PGE 2 is the major and most potent COX metabolite (38) in the kidney, we decided to focus on PGE 2 in the following experiments. PGE 2 enhanced the basolateral organic anion uptake rate, also when COX was inhibited.…”

Section: Discussionmentioning

confidence: 99%

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Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

Sauvant¹,

Holzinger²,

Gekle³

2002

Journal of the American Society of Nephrology

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Abstract. The organic anion transport system of the kidney is of major importance for the excretion of a variety of endogenous compounds, drugs, and potentially toxic substances. The basolateral uptake into proximal tubular cells is mediated by a tertiary active transport system. Epidermal growth factor (EGF) leads to an increase in the basolateral uptake rate of the model substrate para-aminohippuric acid (PAH) in opossum kidney (OK) cells. This stimulation is mediated by successive activation of the mitogen-activated protein kinases, mitogenactivated/extracellular signal-regulated kinase kinase (MEK) and extracellular regulated kinase isoforms 1 and 2 (ERK1/2). This study investigates the regulatory network of EGF action on PAH uptake downstream ERK1/2 in more detail. EGF stimulation of the basolateral uptake rate of [ 14 C]PAH was abolished by the phospholipase A 2 inhibitor AACOCF3. [ 14 C]PAH uptake was enhanced by arachidonic acid. Furthermore, EGF led to an increase in arachidonic acid release and to the generation of prostaglandins. AACOCF3 did not influence EGF-induced ERK1/2 activation, indicating that ERK1/2 is upstream of PLA 2 . In addition, EGF stimulated the influx of extracellular Ca 2ϩ . However, Ca 2ϩ -influx was not required for the stimulatory action of EGF on [ 14 C]PAH uptake. Inhibitors of COX and lipoxygenases reduced [ 14 C]PAH uptake dosedependently, whereas inhibition of cytochrome P450 did not. In the presence of indomethacin, EGF had no stimulatory effect on [ 14 C]PAH uptake. The inhibitory effect of indomethacin was not due to competitive action on PAH uptake. Furthermore, prostaglandin E 2 (PGE 2 ) increased basolateral [ 14 C]PAH uptake rate dose-dependently, and this increase was also observed in the presence of indomethacin. Selective inhibition of COX2 by indomethacin amid or indomethacin n-heptyl ester did not inhibit [ 14 C]PAH uptake, whereas selective inhibition of COX1 dose-dependently inhibited [ 14 C]PAH uptake. This and previous data lead to the conclusion that EGF successively activates MEK, ERK1/2, and PLA 2 , leading to an increased release of arachidonic acid. Subsequently, arachidonic acid is metabolized to prostaglandins via COX1, which then mediate EGF-induced stimulation of basolateral organic anion uptake rate.The organic anion transport system of the renal proximal tubule plays a crucial role in the excretion of a variety of potentially toxic compounds (1). This system consists of a basolaterally located organic anion exchanger and a less well characterized transport step at the apical membrane (2).The basolateral organic anion exchanger is a tertiary active transport system, dependent on an inward-directed Na ϩ -gradient to drive the uptake of ␣-ketoglutarate, which is then exchanged for organic anions (1-4). The basolateral exchanger for organic anions and dicarboxylates was cloned by three independent groups (5-7) in 1997 and named OAT1 (rat), ROAT1 (rat), or fROAT1 (winter flounder). The homologous protein was cloned from human kidney only recently and wa...

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Section: Discussionmentioning

confidence: 99%

“…In the kidney, PGE 2 is the major effective metabolite of the COX pathway (37,38). By HPLC, prostaglandins were shown to be released by EGF.…”

Section: Pge 2 Stimulates Basolateral Pah Uptake Ratementioning

confidence: 99%

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

Sauvant¹,

Holzinger²,

Gekle³

2002

Journal of the American Society of Nephrology

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“…rostaglandins participate in the regulation of the renal circulation 1 and tubular ion transport as well as renin secretion, the latter via a cyclooxygenase-2 (COX-2)-dependent mechanism. 2,3 The constitutive enzyme cyclooxygenase-1 (COX-1) has been identified in the collecting tubules and the renal vasculature.…”

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confidence: 99%

Bradykinin Regulates Cyclooxygenase-2 in Rat Renal Thick Ascending Limb Cells

et al. 2004

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Abstract-Cyclooxygenase-2 (COX-2) is constitutively expressed in a subset of thick ascending limb cells in the cortex and medulla and increases when the renin-angiotensin and kallikrein-kinin systems are activated. Although the contribution of angiotensin II to the regulation of COX-2 is known, the effects of bradykinin on COX-2 expression have not been determined in this nephron segment. We evaluated expression of B2 bradykinin receptors in thick ascending limb cells containing COX-2 and the effect of bradykinin on COX-2 expression in primary cultured medullary thick ascending cells. The presence of B2 receptors was studied in renal sections by immunohistochemistry with antibodies against B2, COX-2, and Tamm-Horsfall glycoprotein. B2 receptors were detected on the apical and basolateral portion of the thick ascending cells. These cells also contained COX-2, suggesting that COX-2 expression may be regulated via B2 receptor. Incubation of cultured medullary thick ascending cells with bradykinin (10 Ϫ7 to 10 Ϫ5 mol/L) induced a significant increase on COX-2 protein expression. Maximal expression of COX-2 was observed 4 hours after exposure to bradykinin (10 Ϫ7 mol/L), effect abolished by a B2 receptor antagonist (HOE-140; 10 Ϫ6 mol/L). Prostaglandin E 2 production increased when these cells were challenged with bradykinin for 4 hours, indicating that COX-2 was enzymatically active. We have demonstrated (1) the presence of B2 receptors in thick ascending limb cells expressing COX-2 and (2) the stimulatory effect of bradykinin on COX-2 protein expression, via B2 receptors, in cultured medullary thick ascending cells. We suggest that bradykinin can affect ion transport in the thick ascending limb via a COX-2-mediated mechanism. Key Words: cyclooxygenase Ⅲ bradykinin Ⅲ immunohistochemistry Ⅲ rats Ⅲ kidney Ⅲ receptors, bradykinin Ⅲ prostaglandins P rostaglandins participate in the regulation of the renal circulation 1 and tubular ion transport as well as renin secretion, the latter via a cyclooxygenase-2 (COX-2)-dependent mechanism. 2,3 The constitutive enzyme cyclooxygenase-1 (COX-1) has been identified in the collecting tubules and the renal vasculature. 4,5 Immunohistochemical localization studies have detected COX-2 in the perimacula densa region and a subset of thick ascending limb (TAL) epithelial cells located in the cortex (cTAL) 6,7 and outer medulla (mTAL) 7 as well as in interstitial medullary cells. 8 COX-2 expression in the kidney under basal conditions suggests that COX-2 may have a physiological role. Expression of the COX-2 isoform is increased in the kidney during development, 9,10 adrenalectomy, 11,12 and low-salt diet 13 ; it is decreased by glucocorticoids. 11,12 The kallikrein-kinin system (KKS) 14 contributes to the regulation of renal blood flow and salt and water excretion. The renal effects of bradykinin under physiological conditions are mediated by the B2 receptor, whereas the B1 receptor is expressed in pathological states such as inflammation. 15 Activation of the renin-angiotensin and KKS ...

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“…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%

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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Eicosanoid regulation of the renal vasculature

Cited by 169 publications

References 167 publications

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells

Bradykinin Regulates Cyclooxygenase-2 in Rat Renal Thick Ascending Limb Cells

Eicosanoids and renal damage in cardiometabolic syndrome

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