Long-term thromboxane-synthase inhibition prolongs survival in murine lupus nephritis

Salvati, Patricia; Lamberti, E.; Ferrario, Roberto; Ferrario, Romana G.; Scampini, Giovanna; Pugliese, Francesco; Barsotti, Paola; Patrono, Carlo

doi:10.1038/ki.1995.166

Cited by 24 publications

(16 citation statements)

References 30 publications

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“…Similar to data in humans, estimates of renal function have been made in the NZBWF1 model of SLE. Numerous reports show that as lupus nephritis progresses, serum creatinine and blood urea nitrogen levels are increased in NZBWF1 mice and that estimates of renal plasma flow are decreased in these mice (5,18,24,42). The present study provides direct evidence that renal blood flow is reduced in SLE mice with renal disease and is consistent with early work using indirect measures of renal hemodynamics.…”

Section: Discussionsupporting

confidence: 80%

“…Like humans with SLE, female NZBWF1 mice exhibit declining renal function with age (5,23,29,42), and we previously reported that these mice develop hypertension with impaired endothelial dependent relaxation and enhanced smooth muscle contraction (40). In addition, chronic treatment of these animals with angiotensin-converting enzyme inhibitors delays the onset of renal injury (7,12), making NZBWF1 mice ideal for examining the renal hemodynamic responses to ANG II.…”

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confidence: 99%

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Blood pressure and renal hemodynamic responses to acute angiotensin II infusion are enhanced in a female mouse model of systemic lupus erythematosus

Venegas-Pont

Mathis

Iliescu

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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-Inflammation and immune system dysfunction contributes to the development of cardiovascular and renal disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that carries a high risk for both renal and cardiovascular disease. While hemodynamic changes that may contribute to increased cardiovascular risk have been reported in humans and animal models of SLE, renal hemodynamics have not been widely studied. The renin-angiotensin system (RAS) plays a central role in renal hemodynamic control, and although RAS blockade is a common therapeutic strategy, the role of RAS in hemodynamic function during SLE is not clear. This study tested whether mean arterial pressure (MAP) and renal hemodynamic responses to acute infusions of ANG II in anesthetized animals were enhanced in an established female mouse model of SLE (NZBWF1). Baseline MAP was not different between anesthetized SLE and control (NZWLacJ) mice, while renal blood flow (RBF) was significantly lower in mice with SLE. SLE mice exhibited an enhanced pressor response and greater reduction in RBF after ANG II infusion. An acute infusion of the ANG II receptor blocker losartan increased RBF in control mice but not in mice with SLE. Renin and ANG II type 1 receptor expression was significantly lower, and ANG II type 2 receptor expression was increased in the renal cortex from SLE mice compared with controls. These data suggest that there are fewer ANG II receptors in the kidneys from mice with SLE but that the existing receptors exhibit an enhanced sensitivity to ANG II. inflammation; angiotensin receptor; autoimmune INFLAMMATION AND IMMUNE SYSTEM dysregulation are recognized as prominent contributors to the development and progression of cardiovascular and renal disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder associated with a high risk for the development of renal and cardiovascular disease, which are major causes of mortality in these patients (43). Almost all patients with SLE have at least some evidence of renal damage on biopsy (4, 11), and measures of declining renal function, including elevated serum creatinine and blood urea nitrogen or reduced filtration fraction, are commonly reported (11,20,28).The renin-angiotensin system (RAS) is well known for its critical role in renal hemodynamic control and blood pressure regulation and is a common therapeutic target in patients with SLE. Although renal dysfunction and blockade of the RAS system are common to patients with SLE, renal hemodynamic responses to ANG II have not been previously investigated. In the present study, we tested the hypothesis that during SLE, there is an enhanced renal hemodynamic response to acute infusion of ANG II. This hypothesis was tested using an experimental mouse model of SLE.The New Zealand Black/White F1 hybrid (NZBWF1) is an established and widely used model of lupus nephritis (8). Like humans with SLE, female NZBWF1 mice exhibit declining renal function with age (5, 23, 29, 42), and we previously reporte...

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Blood pressure and renal hemodynamic responses to acute angiotensin II infusion are enhanced in a female mouse model of systemic lupus erythematosus

Venegas-Pont

Mathis

Iliescu

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Moreover, in other kidney disease models, blockade of TP receptor signaling is typically protective. For example, thromboxane antagonists reduce proteinuria and renal pathology in murine lupus nephritis (27,34,43) and improve renal function in cyclosporine nephrotoxicity (15,24). The reasons for this seemingly paradoxical exaggeration of renal injury in the TP-deficient mice are not clear from our studies.…”

contrasting

confidence: 47%

A role for the thromboxane receptor in l-NAME hypertension

François¹,

Makhanova²,

Ruiz³

et al. 2008

American Journal of Physiology-Renal Physiology

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Actions of the lipid mediator thromboxane (Tx) A2 acting through the TP receptor contribute to the pathogenesis of cardiovascular disease. To further explore the role of TxA2 in hypertension, we examined the consequences of deficiency of the TP receptor on the course of hypertension associated with endothelial dysfunction and salt sensitivity. To this end, the nitric oxide synthase inhibitor N G -nitro-Larginine methyl ester (L-NAME) was administered to TP-deficient (Tp Ϫ/Ϫ ) and wild-type (Tp ϩ/ϩ ) control mice in drinking water for 21 wk along with a high-salt (HS; 6% NaCl) diet. Administration of L-NAME increased urinary excretion of TxB2 to a similar extent in both Tp ϩ/ϩ and Tp Ϫ/Ϫ animals. L-NAME also caused significant and sustained elevations in blood pressure that reached a maximum between weeks 3 and 6. However, the severity of hypertension was attenuated in the Tp Ϫ/Ϫ mice throughout the study period (P Ͻ 0.001). At the end of the study, the wild-type mice developed significant cardiac hypertrophy (23.6 Ϯ 2% increase in heart-to-body weight ratio). The severity of cardiac hypertrophy was attenuated in the TP-deficient group (11.1 Ϯ 2.6%; P Ͻ 0.05). In contrast, kidney hypertrophy was exaggerated in the Tp Ϫ/Ϫ mice compared with controls (37.1 Ϯ 5.4 vs. 12.3 Ϯ 2.3%; P Ͻ 0.01). Moreover, the severity of glomerulosclerosis, tubule vacuolization, and interstitial chronic inflammation was also enhanced in the Tp Ϫ/Ϫ group (P Ͻ 0.01). Thus, in L-NAME hypertension, TP receptors contribute to elevated blood pressure and cardiac hypertrophy. In this model, TP receptors also provided unexpected protection against kidney injury. cardiovascular disease; cardiac hypertrophy; prostanoids; renal injury THROMBOXANE A 2 (TxA 2 ), a product of acid arachidonic metabolism through the cyclooxygenase pathway (COX), is a potent vasoconstrictor and platelet aggregant. TxA 2 acting through its cognate thromboxane-prostanoid (TP) receptor also contributes to cardiovascular pathology including ischemic heart disease (41), atherosclerosis (28), and vascular injury (8). Moreover, an imbalance between TxA 2 and the vasodilator, antithrombotic prostanoid prostacylin (PGI 2 ), has been suggested to be responsible for the increase in cardiovascular risk associated with specific inhibitors of COX-2 (16). In this setting, unrestrained actions of TxA 2 seem to promote the development of cardiovascular disease (11).The TxA 2 -TP pathway has also been implicated in the pathogenesis of hypertension. In this regard, a role for TxA 2 in blood pressure elevation has primarily been established in ANG II-dependent hypertension (30). For example, we and others previously demonstrated contributions of TxA 2 during chronic ANG II infusion (12, 22, 23) or in renovascular hypertension (4, 19). Whether TxA 2 contributes to the pathogenesis of other forms of hypertension is less clear. To address this issue, we compared responses of TP-deficient and wildtype mice to N G -nitro-L-arginine methyl ester (L-NAME) with HS feeding. We find that TP receptor...

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“…Kelley et al (37) first demonstrated enhanced production of TX in kidneys from autoimmune mice. In these murine models, treatment with TX antagonists preserved renal function, reduced glomerular capillary immune complex deposits, and lessened glomerular inflammation (27,38). A similar role for TXA 2 has been demonstrated in transplant rejection.…”

Section: Discussionmentioning

confidence: 78%

Proinflammatory Actions of Thromboxane Receptors to Enhance Cellular Immune Responses

Thomas

Rocha

Nataraj

et al. 2003

The Journal of Immunology

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Metabolism of arachidonic acid by the cyclo-oxygenase (COX) pathway generates a family of prostanoid mediators. Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting COX, thereby reducing prostanoid synthesis. The efficacy of these agents in reducing inflammation suggests a dominant proinflammatory role for the COX pathway. However, the actions of COX metabolites are complex, and certain prostanoids, such as PGE2, in some circumstances actually inhibit immune and inflammatory responses. In these studies, we examine the hypothesis that anti-inflammatory actions of NSAIDs may be due, in part, to inhibition of thromboxane A2 synthesis. To study the immunoregulatory actions of thromboxane A2, we used mice with a targeted disruption of the gene encoding the thromboxane-prostanoid (TP) receptor. Both mitogen-induced responses and cellular responses to alloantigen were substantially reduced in TP−/− spleen cells. Similar attenuation was observed with pharmacological inhibition of TP signaling in wild-type splenocytes, suggesting that reduced responsiveness was not due to subtle developmental abnormalities in the TP-deficient mice. The absence of TP receptors reduced immune-mediated tissue injury following cardiac transplant rejection, an in vivo model of intense inflammation. Taken together, these findings show that thromboxane augments cellular immune responses and inflammatory tissue injury. Specific inhibition of the TP receptor may provide a more precise approach to limit inflammation without some of the untoward effects associated with NSAIDs.

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Long-term thromboxane-synthase inhibition prolongs survival in murine lupus nephritis

Cited by 24 publications

References 30 publications

Blood pressure and renal hemodynamic responses to acute angiotensin II infusion are enhanced in a female mouse model of systemic lupus erythematosus

Blood pressure and renal hemodynamic responses to acute angiotensin II infusion are enhanced in a female mouse model of systemic lupus erythematosus

A role for the thromboxane receptor in l-NAME hypertension

Proinflammatory Actions of Thromboxane Receptors to Enhance Cellular Immune Responses

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