Role of renal cortical cyclooxygenase-2 expression in hyperfiltration in rats with high-protein intake

Yao, Bing; Xu, Jie; Qi, Zhonghua; Harris, Raymond C.; Zhang, Mingzhi

doi:10.1152/ajprenal.00500.2005

Cited by 37 publications

(30 citation statements)

References 39 publications

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“…Although the beneficial effects of COX-2 inhibitors in these models of progressive glomerular injury likely are the result of multiple mechanisms, including inhibition of hyperfiltration (10,27), as well as direct anti-inflammatory effects (28), our studies indicate a potentially pathogenic role for COX-2 metabolites to increase the susceptibility of podocytes to further injury and therefore suggest that podocytes also might be a target for COX-2 inhibitors in progressive glomerular injury. In this regard, Kennedy et al (13) demonstrated that mechanical stretch induced expression of COX-2 and the EP4 subtype of prostaglandin E2 receptor in cultured podocytes, and in the stretched podocytes, prostaglandin E2 administration induced actin stress fiber dissociation.…”

Section: Discussionmentioning

confidence: 77%

Overexpression of Cyclooxygenase-2 Predisposes to Podocyte Injury

Cheng¹,

Wang²,

Jo³

et al. 2007

Journal of the American Society of Nephrology

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Increased podocyte cyclooxygenase-2 (COX-2) expression is seen in rats after renal ablation and Thy-1 nephritis and in cultured murine podocytes in response to mechanical stress. For investigation of whether COX-2 overexpression plays a role in podocyte injury, transgenic B6/D2 mice in which COX-2 expression was driven by a nephrin promoter were established. Selective upregulation of COX-2 expression in podocytes of transgenic mouse kidneys was confirmed by immunoblotting and immunohistochemistry. Whether upregulation of podocyte-specific COX-2 expression enhanced sensitivity to the development of Adriamycin nephropathy was examined. Adriamycin administration induced dramatically more albuminuria and foot process effacement and reduced glomerular nephrin mRNA and immunoreactivity in transgenic mice compared with wild-type littermates. Adriamycin also markedly increased immunoreactive COX-2 expression in podocytes from transgenic mice compared with the wild-type mice. Reverse transcriptase-PCR indicated that this increase represented a stimulation of endogenous COX-2 mRNA expression rather than COX-2 mRNA driven by the nephrin promoter. Balb/C mice, which are susceptible to renal injury by Adriamycin, also increased podocyte COX-2 expression and reduced nephrin expression in response to administration of the drug. Long-term treatment with the COX-2-specific inhibitor SC58236 ameliorated the albuminuria that was induced by Adriamycin in the transgenic mice. SC58236 also reduced Adriamycin-induced foot process effacement in both the COX-2 transgenic mice and Balb/C mice. Therefore, overexpression of COX-2 may predispose podocytes to further injury.

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Section: Discussionmentioning

confidence: 77%

Overexpression of Cyclooxygenase-2 Predisposes to Podocyte Injury

Cheng¹,

Wang²,

Jo³

et al. 2007

Journal of the American Society of Nephrology

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“…Moreover, COX2 inhibition decreases renal hyperfiltration, proteinuria, and glomerulosclerosis in a variety of animal models (28 -30). These effects are thought to be due to COX2 inhibition-mediated reductions in vasodilatory prostaglandins, such as prostacyclin and PGE (30), leading to decreased intraglomerular capillary pressure. Some data support the hypothesis that COX2-derived prostaglandins exert vasodilatory actions at the renal arteriolar level in animals and humans (31,32).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes

et al. 2008

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OBJECTIVE-Studies in animal models suggest that cyclooxygenase-2 (COX2) plays a role in the regulation of the renal microcirculation in diabetes. Accordingly, we examined the role of COX2 in the control of renal hemodynamic function and in the renal response to hyperglycemia in humans with uncomplicated type 1 diabetes. We hypothesized that COX2 inhibition would alleviate the hyperfiltration state and would abrogate the hyperglycemia-mediated rise in glomerular filtration rate (GFR).RESEARCH DESIGN AND METHODS-Renal function was assessed during clamped euglycemia and hyperglycemia on 2 consecutive days before and then again after 14 days of COX2 inhibition using 200 mg celecoxib once daily by mouth. For analysis, the cohort was then divided into two groups based on the baseline GFR: 9 subjects exhibited hyperfiltration (GFR Ն135 ml/min per 1.73 m 2 ), and 12 subjects exhibited normofiltration (GFR Ͻ135 ml/min per 1.73 m 2 ).RESULTS-Under euglycemic conditions, COX2 inhibition resulted in a significant decline in GFR in the hyperfiltration group (150 Ϯ 5 to 139 Ϯ 5 ml/min per 1.73 m 2 ) but increased GFR in the normofiltration group (118 Ϯ 5 to 138 Ϯ 5 ml/min per 1.73 m 2 ). COX2 inhibition did not blunt the hyperglycemia-associated rise in GFR in the normofiltration group and was instead associated with an augmented rise in GFR.CONCLUSIONS-In summary, our results support the hypothesis that COX2 is an important determinant of renal hemodynamic function in subjects with type 1 diabetes. The renal response to COX2 inhibition emphasizes that hyperfiltration and normofiltration are distinct physiological states. Diabetes 57: 688-695, 2008 A lterations in renal hemodynamic function are prevalent in diabetes (1,2) and include increased intraglomerular capillary pressure and hyperfiltration (3-5). Because blockade of the renin angiotensin system (RAS) does not completely normalize hyperfiltration (6), it is clear that other factors are operative in the renal microcirculation in diabetes.Animal studies have examined the role of vasodilatation (7) in the pathogenesis of hyperfiltration. Early work focused on the role of cyclooxygenase (COX)-derived prostanoids, which exert a variety of functions in the kidney, including important vasodilatory effects; however, studies initially used nonspecific COX1/COX2 inhibitors (8). With the discovery of the COX2 isoform and selective COX2 inhibitors, experimental models of diabetes revealed that COX2 expression is increased in the macula densa in this condition and is associated with enhanced production of vasodilatory prostaglandins, RAS activation, and renal hyperfiltration (9). Moreover, in streptozotocininduced diabetic rat models with a renal hyperfiltration phenotype, hyperglycemia-associated prostaglandin production and hyperfiltration were blunted using COX2 inhibition (9). Given the association between renal hyperfiltration, intraglomerular hypertension, and nephropathy related to diabetes (7,10,11), the elucidation of COX2-mediated renal hemodynamic function changes in dia...

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“…It has also been reported that there are important sex-dependent differences in the evolution of renal dysfunction (3,8,11,12,21,22,24,26). Considering the results reported by Yao et al (30) showing that an increase in COX2 may be secondary to an activation of neuronal nitric oxide synthase (nNOS), we also tested the hypothesis that the increments in COX2 elicited by HPI are accompanied by a simultaneous increment in nNOS. Studies to examine whether the previously mentioned hypotheses are correct have been performed in 3-to 4-and 10-to 11-mo-old rats treated with an AT 1 receptor antagonist (ARA) during the nephrogenic period (ARAnp).…”

mentioning

confidence: 91%

“…It was also expected that HPI-induced renal changes are greater in males than in females. These hypotheses are based on studies showing that HPI induces an increase in COX2 (30) and accelerates the progression of renal disease in several models of renal disease (6). It has also been reported that there are important sex-dependent differences in the evolution of renal dysfunction (3,8,11,12,21,22,24,26).…”

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confidence: 99%

Renal effects of prolonged high protein intake and COX2 inhibition on hypertensive rats with altered renal development

Reverte

Tapia²,

Moreno³

et al. 2011

American Journal of Physiology-Renal Physiology

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Reverte V, Tapia A, Moreno JM, Rodríguez L, Salazar F, Llinás MT, Salazar FJ. Renal effects of prolonged high protein intake and COX2 inhibition on hypertensive rats with altered renal development. Am J Physiol Renal Physiol 301: F327-F333, 2011. First published May 25, 2011 doi:10.1152/ajprenal.00110.2011.-Cyclooxygenase 2 (COX2) is involved in regulating renal hemodynamics after renal ablation. It is also known that high protein intake (HPI) leads to a deterioration of renal function when there is preexisting renal disease and that there are important gender differences in the regulation of renal function. This study tested the hypothesis that the role of COX2 in regulating renal function and the renal hemodynamic effects elicited by HPI are enhanced when nephrogenesis is altered during renal development. It was also expected that the role of COX2 and the effects elicited by HPI are age and sex dependent. Newborn Sprague-Dawley rats were treated with an AT1 ANG II receptor antagonist during the nephrogenic period (ARAnp). Experiments were performed at 3-4 and 10 -11 mo of age. Arterial pressure was elevated (P Ͻ 0.05) at both ages and in both sexes of ARAnptreated rats. Renal COX2 expression was only elevated (P Ͻ 0.05) at 10 -11 mo of age in both sexes of ARAnp-treated rats. COX2 inhibition induced greater renal vasoconstriction in male and female hypertensive than in normotensive rats at both ages. HPI did not induce glomerular filtration rate (GFR) in the youngest hypertensive rats and in the oldest female hypertensive rats. However, the GFR decreased during HPI (0.63 Ϯ 0.07 to 0.19 Ϯ 0.05 ml/min) in the oldest male hypertensive rats. The HPI-induced increment in proteinuria was greater (P Ͻ 0.05) in male (99 Ϯ 22 mg/day) than in female (30 Ϯ 8 mg/day) hypertensive rats. These results show that COX2 plays an important role in the regulation of renal function when renal development is altered and that prolonged HPI can lead to a renal insufficiency in males but not in females with reduced nephron endowment.hypertension; proteinuria; renal function SEVERAL STUDIES HAVE PROPOSED that an alteration in nephrogenesis leads to a compensatory glomerular hypertrophy and an accelerated deterioration of renal function that are sex dependent (2,8,21,31). It has been reported that the compensatory glomerular changes that occur in male animals after subtotal ablation of renal mass are mediated by an increase in cyclooxygenase 2 (COX2) activity (7,27). However, it is unknown to what extent COX2 is involved in the regulation of renal function when nephron endowment decreases during renal development and whether this importance of COX2 is greater in males than in females. One hypothesis tested in this study is that COX2-derived metabolites are involved in the regulation of renal function when nephrogenesis is altered during the late nephrogenic period and that the role of COX2 is sex and aging dependent. A sex-dependent difference was expected since it has been reported in other mechanisms involved in the regulation of ren...

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Role of renal cortical cyclooxygenase-2 expression in hyperfiltration in rats with high-protein intake

Cited by 37 publications

References 39 publications

Overexpression of Cyclooxygenase-2 Predisposes to Podocyte Injury

Overexpression of Cyclooxygenase-2 Predisposes to Podocyte Injury

The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes

Renal effects of prolonged high protein intake and COX2 inhibition on hypertensive rats with altered renal development

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