Superoxide Formation and Interaction with Nitric Oxide Modulate Systemic Arterial Pressure and Renal Function in Salt-Depleted Dogs

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Ϫ activity in the kidney, responses to administration of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME; 200 g ⅐ min Ϫ1 ⅐ kg body wt Ϫ1 ) were assessed in knockout mice the lacking NAD(P)H oxidase subunit gp91 phox (KO; n ϭ 10) and in wild-type (WT; n ϭ 10) mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearances, respectively. Baseline RBF was higher in KO compared with WT mice (5.8 Ϯ 0.5 vs. 4.5 Ϯ 0.3 ml ⅐ min Ϫ1 ⅐ g Ϫ1 ; P Ͻ 0.04) without significant differences in GFR (0.62 Ϯ 0.04 vs. 0.73 Ϯ 0.05 ml ⅐ min Ϫ1 ⅐ g Ϫ1 ) and in mean arterial pressure (MAP; 91 Ϯ 6 vs. 88 Ϯ 4 mmHg). L-NAME infusion for 60 min caused similar increases in MAP (114 Ϯ 6 vs. 113 Ϯ 3 mmHg) in both groups but resulted in a lesser degree of reduction in RBF in KO compared with WT mice (Ϫ7 Ϯ 3 vs. Ϫ17 Ϯ 3%; P Ͻ 0.02), although GFR remained unchanged in both groups. The natriuretic response to systemic L-NAME infusion was attenuated in KO compared with WT mice (⌬: 3.1 Ϯ 0.7 vs. 5.2 Ϯ 0.6 mol ⅐ min Ϫ1 ⅐ g Ϫ1 ). L-NAME increased urinary 8-isoprostane excretion rate in WT (5.9 Ϯ 1 to 7.7 Ϯ 1 pg ⅐ min Ϫ1 ⅐ g Ϫ1 ; P Ͻ 0.02) but not in KO mice (5.6 Ϯ 1 to 4.9 Ϯ 0.3 pg ⅐ min Ϫ1 ⅐ g Ϫ1 ). In contrast, responses to another vasoconstrictor, norepinephrine, were similar in both strains of mice. These data indicate that activation of NAD(P)H oxidase results in the enhancement of O 2 Ϫ activity that influences renal hemodynamics and excretory function in the condition of NO deficiency. superoxide; oxidative stress; renal blood flow; sodium excretion; 8-isoprostane excretion CURRENT LITERATURE REVEALS an increasing recognition that the interaction between nitric oxide (NO) and superoxide (O 2 Ϫ ) plays an important role in the physiology as well as in the pathophysiology of kidney function and in hypertension (8,19,(23)(24)(25)42). Most of the evidence suggests that there is a balance between the production of NO and O 2 Ϫ that regulates the body function by opposing each other's action. It was demonstrated in vitro that O 2 Ϫ production was increased during NO inhibition in an isolated aortic strip (11). Enhancement of O 2 Ϫ activity by inhibiting SOD enzymes has been shown to decrease renal blood flow (RBF) and sodium excretion (U Na V; Refs. 8,19,20,24,26), and these responses to SOD inhibition were markedly enhanced during inhibition of the NO synthase (NOS) enzyme (20,24,25

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confidence: 68%

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confidence: 83%

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confidence: 99%

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Reduced renal responses to nitric oxide synthase inhibition in mice lacking the gene for gp91^phoxsubunit of NAD(P)H oxidase

Haque¹,

Majid²

2008

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“…Additionally, other factors may contribute to the stimulation of fibrosis, independent of ANG II (15,16). The sustained formation of peroxynitrite in rats fed a high-salt diet may induce sulfhydryl oxidation, protein nitration, and lipid peroxidation, which all contribute to kidney injury (8), as reflected by the glomerular expansion and tubulointerstitial fibrosis. We reported that an excessively high-salt diet, by itself, leads to a marked increase in peroxynitrite formation and predisposes the kidney to greater tubulointerstitial injury when associated with chronic ANG II infusions (23).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II increases fibronectin and collagen I through the β-catenin-dependent signaling in mouse collecting duct cells

Cuevas

González

Inestrosa

et al. 2015

Cuevas CA, Gonzalez AA, Inestrosa NC, Vio CP, Prieto MC. Angiotensin II increases fibronectin and collagen I through the ␤-catenin-dependent signaling in mouse collecting duct cells. Am J Physiol Renal Physiol 308: F358 -F365, 2015. First published November 19, 2014 doi:10.1152/ajprenal.00429.2014.-The contribution of angiotensin II (ANG II) to renal and tubular fibrosis has been widely reported. Recent studies have shown that collecting duct cells can undergo mesenchymal transition suggesting that collecting duct cells are involved in interstitial fibrosis. The Wnt/␤-catenin signaling pathway plays an essential role in development, organogenesis, and tissue homeostasis; however, the dysregulation of this pathway has been linked to fibrosis. In this study, we investigated whether AT1 receptor activation induces the expression of fibronectin and collagen I via the ␤-catenin pathway in mouse collecting duct cell line M-1. ANG II (10 Ϫ7 M) treatment in M-1 cells increased mRNA, protein levels of fibronectin and collagen I, the ␤-catenin target genes (cyclin D1 and c-myc), and the myofibroblast phenotype. These effects were prevented by candesartan, an AT 1 receptor blocker. Inhibition of the ␤-catenin degradation with pyrvinium pamoate (pyr; 10 Ϫ9 M) prevented the ANG II-induced expression of fibronectin, collagen I, and ␤-catenin target genes. ANG II treatment promoted the accumulation of ␤-catenin protein in a time-dependent manner. Because phosphorylation of glycogen synthase kinase-3␤ (GSK-3␤) inhibits ␤-catenin degradation, we further evaluated the effects of ANG II and ANG II plus pyr on p-ser9-GSK-3␤ levels. ANG II-dependent upregulation of ␤-catenin protein levels was correlated with GSK-3␤ phosphorylation. These effects were prevented by pyr. Our data indicate that in M-1 collecting duct cells, the ␤-catenin pathway mediates the stimulation of fibronectin and collagen I in response to AT 1 receptor activation. pyrvinium pamoate; mouse collecting duct cell; tissue homeostasis ANGIOTENSIN II (ANG II) plays a key role in the development and progression of chronic kidney disease (CKD) (27). It has been shown that increased levels of ANG II and renin in renal tubules after subtotal nephrectomy are pathogenically linked to the development of tubulointerstitial injury (10). In particular, alterations in the ANG type 1 (AT 1 ) receptor, angiotensin-converting enzyme 2 (ACE-2), and the newly described (pro)renin receptor precede the development of renal fibrosis (41). Evidence from in vivo studies has shown that AT 1 receptor antagonists ameliorate renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction (17). Furthermore, in vitro studies indicate that ANG II activates renal cells to produce profibrotic factors and extracellular matrix (ECM) proteins (37, 48, 51). These profibrotic factors lead to tubulointerstitial injury and glomerulosclerosis due to excessive accumulation and deposition of ECM components (3, 49), which are the final manifestations of CKD and renal failure (24). In the kidney...

“…While changes in ET B receptor expression do not account for changes in ET B receptor function, the restoration of ET B receptor function by candesartan may be explained by a variety of potential postreceptor mechanisms related to ET B receptor signaling pathways. ANG II could reduce NO synthase (NOS) activity (42), increase superoxide production (12,18), and stimulate ENaC expression and activity (4,25,28). It is possible that the inhibition of ANG II activity in the kidney by AT 1 blockade could oppose any or all of these effects to reduce ENaC activity, as well as increase the ET B /NOS1 signaling, thus leading to enhancing ET B -dependent natriuresis under these conditions.…”

Section: Discussionmentioning

confidence: 99%

Loss of renal medullary endothelin B receptor function during salt deprivation is regulated by angiotensin II

Kittikulsuth

Pollock

2012

Kittikulsuth W, Pollock JS, Pollock DM. Loss of renal medullary endothelin B receptor function during salt deprivation is regulated by angiotensin II. Am J Physiol Renal Physiol 303: F659 -F666, 2012. First published June 6, 2012 doi:10.1152/ajprenal.00213.2012.-We have recently demonstrated that chronic infusion of exogenous ANG II, which induces blood pressure elevation, attenuates renal medullary endothelin B (ETB) receptor function in rats. Moreover, this was associated with a reduction of ET B receptor expression in the renal inner medulla. The aim of this present work was to investigate the effect of a physiological increase in endogenous ANG II (low-salt diet) on the renal ET system, including ET B receptor function. We hypothesized that endogenous ANG II reduces renal medullary ET B receptor function during low-salt intake. Rats were placed on a low-salt diet (0.01-0.02% NaCl) for 2 wk to allow an increase in endogenous ANG II. In rats on normal-salt chow, the stimulation of renal medullary ET B receptor by ETB receptor agonist sarafotoxin 6c (S6c) causes an increase in water (3.6 Ϯ 0.4 from baseline vs. 10.5 Ϯ 1.3 l/min following S6c infusion; P Ͻ 0.05) and sodium excretion (0.38 Ϯ 0.06 vs. 1.23 Ϯ 0.17 mol/min; P Ͻ 0.05). The low-salt diet reduced the ET B-dependent diuresis (4.5 Ϯ 0.5 vs. 6.1 Ϯ 0.9 l/min) and natriuresis (0.40 Ϯ 0.11 vs. 0.46 Ϯ 0.12 mol/min) in response to acute intramedullary infusion of S6c. Chronic treatment with candesartan restored renal medullary ET B receptor function; urine flow was 7.1 Ϯ 0.9 vs. 15.9 Ϯ 1.7 l/min (P Ͻ 0.05), and sodium excretion was 0.4 Ϯ 0.1 vs. 1.1 Ϯ 0.1 mol/min (P Ͻ 0.05) before and after intramedullary S6c infusion, respectively. Receptor binding assays determined that the sodium-depleted diet resulted in a similar level of ET B receptor binding in renal inner medulla compared with rats on a normal-salt diet. Candesartan reduced renal inner medullary ET B receptor binding (1,414 Ϯ 95 vs. 862 Ϯ 50 fmol/mg; P Ͻ 0.05). We conclude that endogenous ANG II attenuates renal medullary ET B receptor function to conserve sodium during salt deprivation independently of receptor expression. low-salt diet; ETB receptor; renal medulla; renin-angiotensin system; natriuresis THE ENDOTHELIN (ET) and renin-angiotensin system (RAS) play an important role in sodium balance and blood pressure control. ET-1 is highly produced in the kidney, especially by the inner medullary collecting duct (23). ET-1 via ET B receptor activation in the renal medulla stimulates nitric oxide production to facilitate water and sodium excretion (27) via increased renal medullary blood flow (43) and inhibition of epithelial sodium channel activity (ENaC) (8, 9) as well as reabsorption in the medullary thick ascending limb (30). In contrast, ANG II prominently acts as an antinatriuretic hormone at least in part by increasing abundance of sodium transporters and channels along the nephron, mainly mediated by the AT 1 receptordependent pathway (22). Differences in salt intake affect both the ET system ...