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Angiotensin II (ANG II) produced as result of activation of the renin-angiotensin system (RAS) plays a critical role in the pathogenesis of chronic kidney disease via its hemodynamic effects on the renal microcirculation as well as by its nonhemodynamic actions including the production of extracellular matrix proteins such as fibronectin, a multifunctional extracellular matrix protein that plays a major role in cell adhesion and migration as well as in the development of glomerulosclerosis. ETS-1 is an important transcription factor essential for normal kidney development and glomerular integrity. We previously showed that ANG II increases ETS-1 expression and is required for fibronectin production in mesangial cells. In these studies, we determined that ANG II induces phosphorylation of ETS-1 via activation of the type 1 ANG II receptor and that Erk1/2 and Akt/PKB phosphorylation are required for these effects. In addition, we characterized the role of ETS-1 on the transcriptional activation of fibronectin production in mesangial cells. We determined that ETS-1 directly activates the fibronectin promoter and by utilizing gel shift assays and chromatin immunoprecipitation assays identified two different ETS-1 binding sites that promote the transcriptional activation of fibronectin in response to ANG II. In addition, we identified the essential role of CREB and its coactivator p300 on the transcriptional activation of fibronectin by ETS-1. These studies unveil novel mechanisms involved in RAS-induced production of the extracellular matrix protein fibronectin in mesangial cells and establish the role of the transcription factor ETS-1 as a direct mediator of these effects.

Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl salt-sensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaCl) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 +/- 8 vs. 150 +/- 2 mmHg in normal salt diet (0.5% NaCl), P < 0.05], glomerulosclerosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-F(2alpha)-isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-beta (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (-44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg.kg(-1).day(-1)) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-beta1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 +/- 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-beta1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system.

Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl salt-sensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaCl) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 ± 8 vs. 150 ± 2 mmHg in normal salt diet (0.5% NaCI), P < 0.05], glomerulosclerosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-F2α-isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-β (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (-44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg·kg-1·day-1) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-β1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 ± 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-β 1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system. [ABSTRACT FROM AUTHOR]

Maladaptive activation of the renin-angiotensin system (RAS) has been shown to play a critical role in the pathogenesis of chronic kidney disease. Reactive oxygen species (ROS) are critical signals for many of the nonhemodynamic effects of angiotensin II (ANG II). We have demonstrated that ANG II increases mesangial and cortical cyclooxygenase-2 (COX-2) expression and activity via NADPH oxidase-derived ROS. The transcription factor ETS-! (E26 transformation-specific sequence) has been identified as a critical regulator of growth-related responses and inflammation. The present studies were designed to determine: 1) whether ANG II induces ETS-1 expression in vitro in cultured rat mesangial cells and in vivo in rats infused with ANG II; and 2) whether ROS and COX-2 are mediators of ETS-l induction in response to ANG II. Mesangial cells stimulated with ANG II (l0-7 M) exhibited a significant increase in ETS-l expression that was prevented by the angiotensin type 1 receptor blocker candesartan. NADPH oxidase inhibition with dyphenilene iodinium or apocynin also prevented ETS-l induction, establishing the role of ROS as mediators of ETS-1 expression in response to ANG H. COX-2 inhibition prevented ETS-1 expression in response to ANG II, suggesting that COX-2 is required for ETS-1 induction. By utilizing short interfering RNAs against ETS-l, we have also determined that ETS-l is required to induce the production of fibronectin in response to ANG II. Furthermore~ rats infused with ANG LI manifested increased glomerular expression of ETS-!. These studies unveil novel pathways that may play an important role in the pathogenesis of renal injury when RAS is activated. [ABSTRACT FROM AUTHOR]