Sodium excess aggravates hypertension and renal parenchymal injury in rats with chronic NO inhibition

1994 ◽  
Vol 266 (5) ◽  
pp. F697-F705 ◽  
Author(s):  
C. K. Fujihara ◽  
S. M. Michellazzo ◽  
G. de Nucci ◽  
R. Zatz
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Methyl Ester ◽  
Renal Injury ◽  
Systemic Hypertension ◽  
Glomerular Injury ◽  
No Inhibition ◽  
Glomerular Hypertension ◽  
Sodium Overload ◽  
Parenchymal Injury

Chronic nitric oxide (NO) inhibition promotes hypertension and ischemic glomerular injury with only minor glomerulosclerosis (GS). We evaluated the effect of superimposed salt overload, which has been shown to aggravate GS in other models. Fifteen days of treatment with the NO inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) promoted marked arterial and glomerular hypertension, hyporeninemia, and slight renal interstitial expansion, but no glomerular injury. Salt overload slightly exacerbated systemic and glomerular hypertension, promoted albuminuria, interstitial expansion, and glomerular ischemia, and paradoxically reversed hyporeninemia. The angiotensin II inhibitor losartan attenuated glomerular and systemic hypertension and prevented renal injury in these rats. Thirty days of treatment with L-NAME resulted in marked hypertension, hyperreninemia, interstitial expansion, and glomerular ischemia. Concomitant salt overload exacerbated hypertension, interstitial expansion, and ischemia and promoted massive albuminuria, GS, and creatinine retention. Losartan attenuated these effects. Sodium overload aggravates the renal and systemic consequences of chronic NO inhibition by mechanisms that may include paradoxical activation of renin secretion. Interstitial expansion and glomerular ischemia, rather than GS, constitute the chief modalities of renal injury in this model.

scholarly journals Chronic nitric oxide synthase inhibition aggravates glomerular injury in rats with subtotal nephrectomy.

1995 ◽  
Vol 5 (7) ◽  
pp. 1498-1507 ◽  
Author(s):  
C K Fujihara ◽  
G De Nucci ◽  
R Zatz
Keyword(s):  
Nitric Oxide ◽  
Drinking Water ◽  
No Synthase ◽  
Angiotensin Ii Receptor ◽  
Glomerular Injury ◽  
Renal Ablation ◽  
Glomerular Hypertension ◽  
Contrast Group ◽  
Parenchymal Injury ◽  
Structural Injury

Besides its glomerular hemodynamic effects, nitric oxide (NO) inhibits platelet aggregation and mesangial cell proliferation, two mechanisms possibly involved in the pathogenesis of glomerulosclerosis (GS). Chronic NO synthase inhibition in the rat leads to marked arterial hypertension and promotes glomerular and interstitial injury, but only mild GS. In this study, NO synthase blockade by nitro-L-arginine methyl ester (L-NAME) was associated with 5/6 nephrectomy, a well-known model of GS. Sixty-eight adult male Munich-Wistar rats were distributed among four groups: SHAM (no renal ablation or drug treatment), NX (5/6 nephrectomy), NX+NAME (5/6 nephrectomy and chronic treatment with L-NAME, 5 mg/dL in drinking water) and NX+NAME+L (as in group NX+NAME but also receiving the angiotensin II receptor inhibitor Losartan potassium (L), 25 mg/dL in drinking water). One week after ablation, rats of Group NX showed moderate glomerular hypertension and hypertrophy. Although glomerular enlargement was also modest in Group NX+NAME, glomerular hypertension was particularly severe in this group. Both alterations were absent in Group NX+NAME+L. Only incipient glomerular and interstitial injury occurred at this phase. Three weeks after ablation, renal structural injury was still modest in Group NX. By contrast, Group NX+NAME exhibited marked GS, glomerular ischemic injury, interstitial expansion, and creatinine retention. Renal injury was largely prevented in Group NX+NAME+L. Tuft enlargement occurred in all groups but was most prominent in Group NX. NO synthase inhibition aggravates parenchymal injury and functional impairment in the remanent kidney by mechanisms that may involve glomerular hypertension and renin-angiotensin activation but that appear to be unrelated to glomerular enlargement.

scholarly journals Systemic Aldosterone, But Not Angiotensin II, Plays a Pivotal Role in the Pathogenesis of Renal Injury in Chronic Nitric Oxide-Deficient Male Rats

Endocrinology ◽  
2015 ◽  
Vol 156 (7) ◽  
pp. 2657-2666 ◽  
Author(s):  
Takaichi Suehiro ◽  
Kazuhiko Tsuruya ◽  
Hirofumi Ikeda ◽  
Jiro Toyonaga ◽  
Shunsuke Yamada ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Nitric Oxide Synthase ◽  
Renal Injury ◽  
Male Rats ◽  
Systemic Hypertension ◽  
Type I ◽  
Ang Ii ◽  
Aldosterone Antagonist ◽  
Oxide Synthase

Chronic inhibition of nitric oxide synthase by Nω-nitro-L-arginine methyl ester (L-NAME) causes progressive renal injury and systemic hypertension. Angiotensin II (Ang II) has been conventionally regarded as one of the primary causes of renal injury. We reported previously that such renal injury was almost completely suppressed by both an Ang II type I receptor blocker and an aldosterone antagonist. The aldosterone antagonist also inhibited the systemic Ang II elevation. Therefore, it remains to be elucidated whether Ang II or aldosterone directly affects the development of such renal injury. In the present study, we investigated the role of aldosterone in the pathogenesis of renal injury induced by L-NAME-mediated chronic nitric oxide synthase inhibition in male Wistar rats (aged 10 wk). Serial analyses demonstrated that the renal injury and inflammation in L-NAME-treated rats was associated with elevation of both Ang II and aldosterone. To investigate the direct effect of aldosterone on the renal injury, we conducted adrenalectomy (ADX) and aldosterone supplementation in L-NAME-treated rats. In ADX rats, aldosterone was undetectable, and renal injury and inflammation were almost completely prevented by ADX, although systemic and local Ang II and blood pressure were still elevated. Aldosterone supplementation reversed the beneficial effect of ADX. The present study indicates that aldosterone rather than Ang II plays a central and direct role in the pathogenesis of renal injury by L-NAME through inflammation, independent of its systemic hemodynamic effects.

scholarly journals Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia

2008 ◽  
Vol 295 (4) ◽  
pp. F1134-F1141 ◽  
Author(s):  
Laura G. Sánchez-Lozada ◽  
Virgilia Soto ◽  
Edilia Tapia ◽  
Carmen Avila-Casado ◽  
Yuri Y. Sautin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Uric Acid ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Systemic Hypertension ◽  
Sprague Dawley ◽  
Renal Vasoconstriction ◽  
Renal Abnormalities ◽  
Oxonic Acid

Endothelial dysfunction is a characteristic feature during the renal damage induced by mild hyperuricemia. The mechanism by which uric acid reduces the bioavailability of intrarenal nitric oxide is not known. We tested the hypothesis that oxidative stress might contribute to the endothelial dysfunction and glomerular hemodynamic changes that occur with hyperuricemia. Hyperuricemia was induced in Sprague-Dawley rats by administration of the uricase inhibitor, oxonic acid (750 mg/kg per day). The superoxide scavenger, tempol (15 mg/kg per day), or placebo was administered simultaneously with the oxonic acid. All groups were evaluated throughout a 5-wk period. Kidneys were fixed by perfusion and afferent arteriole morphology, and tubulointerstitial 3-nitrotyrosine, 4-hydroxynonenal, NOX-4 subunit of renal NADPH-oxidase, and angiotensin II were quantified. Hyperuricemia induced intrarenal oxidative stress, increased expression of NOX-4 and angiotensin II, and decreased nitric oxide bioavailability, systemic hypertension, renal vasoconstriction, and afferent arteriolopathy. Tempol treatment reversed the systemic and renal alterations induced by hyperuricemia despite equivalent hyperuricemia. Moreover, because tempol prevented the development of preglomerular damage and decreased blood pressure, glomerular pressure was maintained at normal values as well. Mild hyperuricemia induced by uricase inhibition causes intrarenal oxidative stress, which contributes to the development of the systemic hypertension and the renal abnormalities induced by increased uric acid. Scavenging of the superoxide anion in this setting attenuates the adverse effects induced by hyperuricemia.

scholarly journals Curcumin Induces Nrf2 Nuclear Translocation and Prevents Glomerular Hypertension, Hyperfiltration, Oxidant Stress, and the Decrease in Antioxidant Enzymes in 5/6 Nephrectomized Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Edilia Tapia ◽  
Virgilia Soto ◽  
Karla Mariana Ortiz-Vega ◽  
Guillermo Zarco-Márquez ◽  
Eduardo Molina-Jijón ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Protective Effect ◽  
Renal Injury ◽  
Nuclear Translocation ◽  
Interstitial Fibrosis ◽  
Oxidant Stress ◽  
Systemic Hypertension ◽  
Glomerular Sclerosis ◽  
Renal Ablation ◽  
Glomerular Hypertension

Renal injury resulting from renal ablation induced by 5/6 nephrectomy (5/6NX) is associated with oxidant stress, glomerular hypertension, hyperfiltration, and impaired Nrf2-Keap1 pathway. The purpose of this work was to know if the bifunctional antioxidant curcumin may induce nuclear translocation of Nrf2 and prevents 5/6NX-induced oxidant stress, renal injury, decrease in antioxidant enzymes, and glomerular hypertension and hyperfiltration. Four groups of rats were studied: (1) control, (2) 5/6NX, (3) 5/6NX+CUR,and (4) CUR (n=8–10). Curcumin was given by gavage to NX5/6+CURand CUR groups (60 mg/kg/day) starting seven days before surgery. Rats were studied 30 days after NX5/6 or sham surgery. Curcumin attenuated 5/6NX-induced proteinuria, systemic and glomerular hypertension, hyperfiltration, glomerular sclerosis, interstitial fibrosis, interstitial inflammation, and increase in plasma creatinine and blood urea nitrogen. This protective effect was associated with enhanced nuclear translocation of Nrf2 and with prevention of 5/6NX-induced oxidant stress and decrease in the activity of antioxidant enzymes. It is concluded that the protective effect of curcumin against 5/6NX-induced glomerular and systemic hypertension, hyperfiltration, renal dysfunction, and renal injury was associated with the nuclear translocation of Nrf2 and the prevention of both oxidant stress and the decrease of antioxidant enzymes.

Effect of interactions between nitric oxide and angiotensin II on pressure diuresis and natriuresis

1997 ◽  
Vol 273 (5) ◽  
pp. R1676-R1682 ◽  
Author(s):  
María Isabel Madrid ◽  
Miguel García-Salom ◽  
Jerónimo Tornel ◽  
Marc De Gasparo ◽  
Francisco J. Fenoy
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Renal Function ◽  
Angiotensin Ii ◽  
Methyl Ester ◽  
Perfusion Pressure ◽  
Renal Perfusion ◽  
Angiotensin Receptors ◽  
Water Excretion ◽  
Renal Perfusion Pressure

The present study examined the effect of an angiotensin II AT1 or AT2 receptor antagonist on the impairment of the pressure diuresis and natriuresis response produced by nitric oxide (NO) synthesis blockade. N ω-nitro-l-arginine methyl ester (l-NAME, 37 nmol ⋅ kg−1 ⋅ min−1) lowered renal blood flow and reduced the slopes of the pressure diuresis and natriuresis responses by 44 and 40%, respectively. Blockade of AT1 receptors with valsartan increased slightly sodium and water excretion at low renal perfusion pressure (RPP). Blockade of AT2 receptors with PD-123319 had no effect on renal function. The administration of valsartan or PD-123319 to rats given l-NAME had no effect on the renal vasocontriction induced by NO synthesis blockade. In addition, in rats givenl-NAME, valsartan elevated baseline excretory values at all RPP studied, but it had no effect on the sensitivity of the pressure diuresis and natriuresis response. However, the administration of PD-123319 tol-NAME-pretreated rats shifted the slopes of the pressure diuresis and natriuresis responses toward control values, indicating that the impairment produced by NO synthesis blockade on pressure diuresis is dependent on the activation of AT2 angiotensin receptors.

scholarly journals Angiotensin II and Prostaglandin Interactions on Systemic and Renal Effects of L-NAME in Humans

2001 ◽  
Vol 12 (8) ◽  
pp. 1706-1712
Author(s):  
PATRIZIA PERINOTTO ◽  
ALMERINA BIGGI ◽  
NICOLETTA CARRA ◽  
ANTONELLA ORRICO ◽  
GIUSEPPE VALMADRE ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Methyl Ester ◽  
Excretion Rate ◽  
Renal Plasma Flow ◽  
Nitric Oxide Synthesis ◽  
Renal Effects ◽  
Renal Changes ◽  
Endogenous Prostaglandins

Abstract. For investigation of whether interactions between prostaglandins and angiotensin II modulate renal response to acute nitric oxide synthesis inhibition in humans, seven young volunteers who were kept on a 240-mM Na diet underwent four experiments with 90 min of infusion of 3.0 μg/kg.min-1 NG-nitro-L-arginine methyl ester (L-NAME), each preceded by a 3-d treatment with placebo (PL), 50 mg of losartan (LOS), 75 to 125 mg of indomethacin (IND), or both drugs. Mean arterial pressure (MAP), GFR, effective renal plasma flow (ERPF), and Na excretion rate (UNaV) were measured at baseline and from 0 to 45 min and 45 to 90 min of L-NAME infusion. After PL, L-NAME reduced GFR by 5% at 45 min (P < 0.05) and by 9% at 90 min (P < 0.001), ERPF by 11 to 17% (P < 0.001), and UNaV by 28 to 45% (P < 0.001). MAP, unchanged at 45 min, rose by 5% (P < 0.001) at 90 min. LOS prevented pressor but not renal effects of L-NAME. With L-NAME+IND, MAP rose even at 45 min (+5%; P < 0.001 versus baseline) with a 10% rise at 90 min (P < 0.001). Changes in GFR (-13 to -20%), ERPF (-19 to -26%), and UNaV (-51 to -70%) were greater than those with L-NAME+PL or L-NAME+LOS (P < 0.05 to 0.001). With L-NAME+IND+LOS, MAP did not increase, and GFR, ERPF, and UNaV fell much less than with L-NAME+IND alone (P < 0.02 to 0.001) with no differences versus PL or LOS alone. Angiotensin II blockade does not affect renal changes caused by L-NAME but prevents their potentiation by prostaglandin inhibition. Thus, endogenous prostaglandins counteract renal actions of endogenous angiotensin II in Na-repleted humans even when nitric oxide synthesis is inhibited.

scholarly journals Combined Mycophenolate Mofetil and Losartan Therapy Arrests Established Injury in the Remnant Kidney

2000 ◽  
Vol 11 (2) ◽  
pp. 283-290
Author(s):  
CLARICE KAZUE FUJIHARA ◽  
IRENE DE LOURDES NORONHA ◽  
DENISE MARIA AVANCINI COSTA MALHEIROS ◽  
GLÁUCIA RUTIGLIANO ANTUNES ◽  
IVONE BRAGA DE OLIVEIRA ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Angiotensin Ii ◽  
Renal Injury ◽  
Renal Scarring ◽  
Macrophage Infiltration ◽  
Once Daily ◽  
Glomerular Hypertension ◽  
Angiotensin Ii Antagonists ◽  
Interstitial Disease ◽  
Remnant Kidney

Previously it was shown that early treatment with mycophenolate mofetil (MMF) attenuated renal inflammation, glomerulosclerosis (GS), and interstitial expansion in the 5/6 ablation (NX) model. Angiotensin II antagonists also mitigate renal injury in NX, presumably by lowering glomerular pressure (PGC). This study investigated: (1) whether combined MMF/angiotensin II antagonists treatment affords superior protection compared with the respective monotherapies; and (2) whether this association is effective even when instituted late in the course of the disease. Adult male Munich-Wistar rats underwent NX, remaining untreated for 30 d. BP, albuminuria, and the extent of GS, interstitial expansion, and macrophage infiltration were then determined in 17 rats. The remaining 118 rats received either inert vehicle or one of the following: MMF, 10 mg/kg by gavage once daily; losartan potassium (L), 20 mg/dl in drinking water; or combined MMF/L treatment. Sixty days after ablation, untreated NX rats exhibited marked glomerular hypertension, which was attenuated by MMF and, more effectively, by either L or combined MMF/L treatment. At 120 d, hypertension and albuminuria were worsened in untreated NX rats, which exhibited intense macrophage infiltration and severe glomerular and interstitial disease. L and, to a lesser extent, MMF monotherapies attenuated these abnormalities, without preventing their progression. In rats given combined MMF/L therapy, macrophage infiltration, GS, and interstitial expansion remained at pretreatment levels. By acting on two distinct pathogenic mechanisms, combined MMF/L treatment arrested established renal injury in the NX model. Further investigation is needed to determine whether this association can prevent renal scarring in other models and in human disease.

Effects of acute and chronic l-arginine treatment in experimental hyperuricemia

2007 ◽  
Vol 292 (4) ◽  
pp. F1238-F1244 ◽  
Author(s):  
Laura G. Sánchez-Lozada ◽  
Edilia Tapia ◽  
Rubén López-Molina ◽  
Tomás Nepomuceno ◽  
Virgilia Soto ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Chronic Administration ◽  
Systemic Blood Pressure ◽  
Acute Effect ◽  
Systemic Hypertension ◽  
Afferent Arteriole ◽  
Sprague Dawley ◽  
Structural Alterations ◽  
Renal Vasoconstriction ◽  
Glomerular Hypertension

Experimental hyperuricemia (HU) results in preglomerular arteriolopathy, cortical vasoconstriction, and glomerular hypertension. Recently, uric acid has been shown to induce endothelial dysfunction. We therefore studied the effect of acute and chronic administration of l-arginine (a substrate for endothelial nitric oxide synthase) on the renal hemodynamic and vascular structural alterations induced by HU. To induce HU, oxonic acid (OA; 750 mg·kg−1·day−1) was administered in male Sprague-Dawley rats. To study the acute effect of arginine, nine rats received l-arginine (l-Arg; 15 mg·kg−1·min−1) during micropuncture. To elucidate the chronic effect of l-Arg, OA + 1% l-Arg ( n = 8) and OA + 2.5% l-Arg ( n = 6; drinking water) were evaluated throughout the 5-wk period. Eight normal control (N), and eight OA, rats were also studied. Kidneys were fixed by perfusion and afferent arteriole morphology was evaluated. HU rats developed the renal functional and structural alterations described and had suppressed urinary excretion of NO2−/NO3−. Acute stimulation of nitric oxide (NO) synthesis markedly increased urinary NO2−/NO3−, lowered systemic blood pressure, and relieved cortical vasoconstriction despite a significant increment of glomerular hypertension and afferent arteriole damage. Increasing doses of chronic l-Arg were associated with increasing excretion of urinary NO2−/NO3−, reduction of systemic hypertension, and prevention of cortical vasoconstriction (2.5% l-Arg). In addition, both doses prevented glomerular hypertension and preglomerular arteriolopathy. Thus an acute relief of renal vasoconstriction in the setting of afferent arteriole damage cannot reverse glomerular hypertension, likely due to impairment in preglomerular autoregulation. On the other hand, chronic l-Arg preserved arteriolar structures probably mediated by the antiproliferative effect of NO on vascular smooth muscle cells.

scholarly journals Chronic ouabain treatment induces vasa recta endothelial dysfunction in the rat

2009 ◽  
Vol 296 (1) ◽  
pp. F98-F106 ◽  
Author(s):  
Chunhua Cao ◽  
Kristie Payne ◽  
Whaseon Lee-Kwon ◽  
Zhong Zhang ◽  
Sun Woo Lim ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Methyl Ester ◽  
Endothelial Dysfunction ◽  
Chronic Exposure ◽  
Renal Medulla ◽  
Renal Vasculature ◽  
Vasa Recta

Descending vasa recta (DVR) are 15-μm vessels that perfuse the renal medulla. Ouabain has been shown to augment DVR endothelial cytoplasmic Ca2+ ([Ca2+]CYT) signaling. In this study, we examined the expression of the ouabain-sensitive Na-K-ATPase α2 subunit in the rat renal vasculature and tested effects of acute ouabain exposure and chronic ouabain treatment on DVR. Immunostaining with antibodies directed against the α2 subunit verified its expression in both DVR pericytes and endothelium. Acute application of ouabain (100 or 500 nM) augmented the DVR nitric oxide generation stimulated by acetylcholine (ACh; 10 μM). At a concentration of 1 mM, ouabain constricted microperfused DVR, whereas at 100 nM, it was without effect. Acute ouabain (100 nM) did not augment constriction by angiotensin II (0.5 or 10 nM), whereas l-nitroarginine methyl ester-induced contraction of DVR was slightly enhanced. Ouabain-hypertensive (OH) rats were generated by chronic ouabain treatment (30 μg·kg−1·day−1, 5 wk). The acute endothelial [Ca2+]CYT elevation by ouabain (100 nM) was absent in DVR endothelia of OH rats. The [Ca2+]CYT response to 10 nM ACh was also eliminated, whereas the response to 10 μM ACh was not. The endothelial [Ca2+]CYT response to bradykinin (100 nM) was significantly attenuated. We conclude that endothelial responses may offset the ability of acute ouabain exposure to enhance DVR vasoconstriction. Chronic exposure to ouabain, in vivo, leads to hypertension and DVR endothelial dysfunction, manifested as reduced [Ca2+]CYT responses to both ouabain- and endothelium-dependent vasodilators.

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