Effect of Cyclooxygenase-2 Inhibition on Renal Function After Renal Ablation

Sánchez, Pedro López; Salgado, Luis M.; Ferreri, Nicholas R.; Escalante, Bruno

doi:10.1161/01.hyp.34.4.848

Cited by 66 publications

(53 citation statements)

References 36 publications

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“…As we previously showed [17], 14 days after 5/6 nephrectomy urinary protein excretion was increased from 32.2 ± 5.8 to 102.84 ± 37.32 mg/24h (p = 0.001), this effect persisted for the following 6 weeks (Figure 1(a)). Also SBP was increased from 112.6 ± 12.5 mmHg to 191.8 ± 12.7 mmHg compared with SO rats, 60 days after 5/6 nephrectomy (p < 0.001).…”

Section: Ras Blockade Effect On Renal Functional Parameterssupporting

confidence: 73%

Renin-angiotensin system blockade: Effect on renal mRNA expression in 5/6 nephrectomized rats

Cruz-Laguna¹,

Gámez-Méndez²,

Vargas‐Robles³

et al. 2013

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The aim of this study was to determinate the gene expression levels of angiotensinogen, angiotensin converting enzyme, renin, (pro)renin receptor, and the final rennin-angiotensin system (RAS) products Angiotensin (Ang) II and Ang 1-7 in the remnant kidney of 5/6 nephrectomized rats and its response to RAS pharmacological blockade. Male Wistar rats were divided into five groups: sham operated (SO), 5/6 nephrectomized (NFX), NFX + captopril (50 mg/ kg/day), NFX + losartan (10 mg/kg/day), and NFX + aliskiren (10 mg/kg/day). Animals were followed up for 60 days and protein urine excretion was measured. Systolic blood pressure, renal tissue RAS mRNA expression levels, plasma Ang II, and plasma Ang 1-7 were evaluated at day 60 after nephrectomy. Blood pressure and urine protein were increased after 5/6 nephrectomy. Ang II levels were increased 9.4 fold, whereas Ang 1-7 decreased 72.9% in NFX animals compared with SO rats. 5/6 nephrectomy increased renal angiotensinogen and (pro)renin receptor mRNA expression but down-regulated renin mRNA expression. RAS blockade restored the systolic blood pressure to normal values and slowed down urinary protein excretion, and also prevented changes in Ang II and Ang 1-7. RAS blockade reduced (pro)renin receptor, ACE, and AGT mRNA expression in the remnant kidney. However, renin mRNA expression increased compared with NFX rats. In conclusion these results suggest that inhibition of Ang II synthesis by RAS blockade is associated with renal regulation of RAS mRNA expression and this may be through a mechanism related with the Ang II/Ang 1-7 balance.

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Section: Ras Blockade Effect On Renal Functional Parameterssupporting

confidence: 73%

Renin-angiotensin system blockade: Effect on renal mRNA expression in 5/6 nephrectomized rats

Cruz-Laguna¹,

Gámez-Méndez²,

Vargas‐Robles³

et al. 2013

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“…Previous studies reported that chronic administration of a selective COX2 inhibitor significantly decreased proteinuria and attenuated development of glomerular sclerosis in rats with reduced renal mass. [43][44][45] However, in our study, celecoxib, administered 1 month after Nx, did not significantly improve renal function in the uremic rats with SHPT. Delayed celecoxib treatment after Nx may contribute to the less-protective effect on renal function.…”

Section: Basic Research Wwwjasnorgcontrasting

confidence: 73%

Cyclooxygenase 2 Promotes Parathyroid Hyperplasia in ESRD

Zhang

Qiu

et al. 2011

Journal of the American Society of Nephrology

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Hyperplasia of the PTG underlies the secondary hyperparathyroidism (SHPT) observed in CKD, but the mechanism underlying this hyperplasia is incompletely understood. Because aberrant cyclooxygenase 2 (COX2) expression promotes epithelial cell proliferation, we examined the effects of COX2 on the parathyroid gland in uremia. In patients with ESRD who underwent parathyroidectomy, clusters of cells within the parathyroid glands had increased COX2 expression. Some COX2-positive cells exhibited two nuclei, consistent with proliferation. Furthermore, nearly 78% of COX2-positive cells expressed proliferating cell nuclear antigen (PCNA). In the 5/6-nephrectomy rat model, rats fed a high-phosphate diet had significantly higher serum PTH levels and larger parathyroid glands than sham-operated rats. Compared with controls, the parathyroid glands of uremic rats exhibited more PCNA-positive cells and greater COX2 expression in the chief cells. Treatment with COX2 inhibitor celecoxib significantly reduced PCNA expression, attenuated serum PTH levels, and reduced the size of the glands. In conclusion, COX2 promotes the pathogenesis of hyperparathyroidism in ESRD, suggesting that inhibiting the COX2 pathway could be a potential therapeutic target. Secondary hyperparathyroidism (SHPT) is one of the most common abnormalities of mineral metabolism in patients with chronic kidney disease (CKD), characterized by hyperplasia of the parathyroid gland (PTG). 1 It is well documented that increased parathyroid hormone (PTH) contributes to bone disorders and cardiovascular complications of ESRD patients and is associated with the morbidity and mortality of this population. 2,3 Strong evidence indicates that PTG hyperplasia is positively linked to the magnitude of circulating levels of PTH, and the size of the PTG is associated with the controllability of parathyroid function in CKD patients. 4,5 The mechanism underlying PTG hyperplasia is incompletely defined.Under normal conditions, the turnover rate of the PTG is very low, and mitoses are seldom observed. 1,6 However, under certain pathologic conditions such as CKD, hyperphosphatemia, and vitamin D deficiency, increased proliferation of the PTG can be detected. 7,8 In CKD patients, the PTG shows diffuse and polyclonal proliferation at early stages of SHPT. With progression of the disease, the PTG can transform with monoclonal and aggressive proliferation. 9 -11 It is well accepted that PTG hyperplasia is associated with reduced 1,25-vitamin

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“…Selective increases in renal cortical COX-2 expression can be detected in the region of the MD in rat remnant kidneys without significant alterations in COX-1 expression (105)(106)(107) and from kidneys with streptozotocin-induced diabetes (108,109). Isolated glomeruli from remnant kidneys also demonstrated selective increases in COX-2 immunoreactivity and increased PGE 2 production, which was inhibited by a COX-2 selective inhibitor (105).…”

Section: Effects Of Cox-2 Inhibitors In Proteinuric Statesmentioning

confidence: 99%

“…Chronic administration of a selective COX-2 inhibitor significantly decreased proteinuria and inhibited development of glomerular sclerosis in rats with reduced functioning renal mass (105,106,119). These effects were seen in the absence of any detectable changes in systemic BP, suggesting that any "renoprotective" effects that were seen with the COX-2 inhibitor were not secondary to modulation of systemic BP (105,120).…”

Section: Effects Of Cox-2 Inhibitors In Proteinuric Statesmentioning

confidence: 99%

Update on Cyclooxygenase-2 Inhibitors

Harris

Breyer

2006

Clinical Journal of the American Society of Nephrology

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Nonsteroidal anti-inflammatory drugs represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described side effects can limit their use. Cyclooxygenase-2 (COX-2) inhibitors were initially touted as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of nonspecific nonsteroidal anti-inflammatory drugs. However, in the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion, and maintenance of renal blood flow. This review summarizes the current state of knowledge about both renal and cardiovascular side effects that are attributed to COX-2 selective inhibitors.Clin J Am Soc Nephrol 1: 236 -245, 2006236 -245, . doi: 10.2215 N onsteroidal anti-inflammatory drugs (NSAID) are the most commonly used class of medications for the treatment of pain and inflammation and represent one of the most common classes of medications used worldwide, with an estimated usage of Ͼ30 million per day (1). Nonselective NSAID inhibit both constitutive cyclooxygenase-1 (COX-1) and inducible cyclooxygenase-2 (COX-2), the rate-limiting enzymes that are involved in production of prostaglandins and thromboxane. In addition to their role in inflammation, prostaglandins are important regulators of vascular tone, salt and water balance, and renin release, and nonselective NSAID exhibit adverse effects, including salt retention and reduced GFR, which may elevate BP or make pre-existing hypertension worse (2). It has been estimated that as many as 2.5 million Americans experience NSAID-mediated renal effects yearly (3). Risk factors that predispose to NSAID-induced renal functional alterations include age Ͼ65 yr, cardiovascular disease, diabetes, male gender, high NSAID dosage, and concurrent use of other nephrotoxic drugs (3). Up to 20% of patients who take nonselective NSAID and have more than one of these risk factors may manifest alterations in renal function.In addition to renal side effects, nonselective NSAID have long been known to predispose to gastrointestinal (GI) toxicity. It has been estimated that one third of patients who taking long-term nonselective NSAID develop endoscopically proven gastric or duodenal ulcers (4). The risk for serious bleeding from these lesions is somewhat lower, with approximately 100,000 hospitalizations for GI complications of NSAID (5). One study estimated that nonselective NSAID-induced GI abnormalities constitute the 15th leading cause of death in the United States (6). The premise that COX-1 performs cellular "housekeeping" functions for normal physiologic activity and is the predominant isoform expressed in platelets and the GI tract, whereas COX-2 acts at inflammatory sites, led to the development of COX-2 selective inhibitors. It also was originally hypothesized that the renal effects of nonselective NSAID were also linked to COX-...

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Effect of Cyclooxygenase-2 Inhibition on Renal Function After Renal Ablation

Cited by 66 publications

References 36 publications

Renin-angiotensin system blockade: Effect on renal mRNA expression in 5/6 nephrectomized rats

Renin-angiotensin system blockade: Effect on renal mRNA expression in 5/6 nephrectomized rats

Cyclooxygenase 2 Promotes Parathyroid Hyperplasia in ESRD

Update on Cyclooxygenase-2 Inhibitors

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