Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Blockade of the renin-angiotensin system (RAS) prevents the increase in blood pressure (BP) induced by chronic administration of NG-nitro L-arginine methyl ester (L-NAME) in rats. In the present study, we showed how a converting enzyme inhibitor can prevent the end-stage tissue damage due to chronic nitric oxide (NO) synthase blockade and thus improve the survival rate. Three experiments were performed. In the first, rats (n = 10) were given L-NAME (50 mg/kg) and 10 other rats were given L-NAME plus quinapril (10 mg/kg) starting 1 month after L-NAME administration. Ten untreated rats were used as controls. Rats were killed after 2 months, and the RAS, renal function, and renal morphology were analyzed. In the second experiment, a similar protocol was used, and function and morphological damage in renal slices and cervical medullary tissue were assessed after 4 months of L-NAME and 3 months of quinapril + L-NAME. In the third experiment, a similar protocol was used, but to establish survival curves, the animals were not killed. L-NAME significantly increased BP without causing any significnat changes in plasma renin activity (PRA) at 2 months. The aortic wall cyclic GMP content was significantly decreased, and the angiotensin-converting enzyme (ACE) activity was increased by L-NAME. Quinapril significantly reversed the high BP induced by L-NAME without changing the decrease in the aortic wall cyclic GMP. Two-month L-NAME treatment decreased renal function and damaged renal tissue. Quinapril prevented both proteinuria and morphological damage. Four-month L-NAME treatment induced renal end-stage damage and infarctions of the cervical medulla. Quinapril prevented this end-stage damage in the kidney and cervical medulla. Quinapril therefore prevented the increased mortality due to L-NAME. Hence, inhibition of ACE, despite its lack of effect on arterial wall cyclic GMP, does reverse the hypertension and prevent end-stage vascular damage induced by chronic L-NAME in target organs.
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PMID:Improved survival in rats administered NG-nitro L-arginine methyl ester due to converting enzyme inhibition. 879 48

The present study was undertaken to investigate whether the development of proteinuria in the borderline hypertensive rat (BHR) is influenced by the Y chromosome and to determine if the onset of proteinuria in the BHR is delayed when blood pressure is lowered with enalapril, an angiotensin I converting enzyme inhibitor. Male F1, rats were the first-generation offspring of the mating of spontaneously hypertensive (SHR) females and Wistar-Kyoto (WKY) males and the mating of SHR males and WKY females. At 20 weeks of age, enalapril (125 mg/l) was added to the drinking water. Untreated BHR and enalapril-treated BHR (BHRE) were followed to 90-100 weeks of age. Urine was collected every 10-20 weeks for determination of protein, albumin, and nitric oxide (NO2/NO3) metabolite excretion. Indirect blood pressure in BHR from both crosses was approximately 175 mm Hg from 20 to 90-100 weeks of age. Enalapril lowered blood pressure by about 30 mm Hg, but was ineffective in reducing urinary protein or albumin excretion rates at any age. Urinary excretion of nitric oxide metabolites was similar in all groups at all time periods. There were significant differences in the percent of glomerulosclerosis between the two matings. Based on these results, renal injury in the BHR is not associated with the Y chromosome and can be dissociated from hypertension. Further studies using congenic and transgenic technology will be necessary to identify functions of genes and associations with hypertension in order to understand the kidney disease in this model of hypertension.
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PMID:Sex chromosomes do not influence renal injury in borderline hypertensive rats. 885 66

The effects of the administration of either the angiotensin converting enzyme (ACE) inhibitor, quinapril (10 mg/kg/day, orally), or the calcium antagonist, diltiazem (100 mg/kg/day, orally), on blood pressure (BP), renal function, and vascular reactivity in isolated perfused mesenteric beds were studied in rats treated for 8 weeks with the nitric oxide (NO) synthesis inhibitor, NG-nitro-L-arginine methyl ester (LNAME, 40 mg/kg/day). The oral administration of LNAME significantly increased systolic BP values, which reached the levels of 186 +/- 7 mm Hg at week 8. Both quinapril and diltiazem reduced this, although the ACE inhibitor was more effective than the calcium antagonist. The chronic inhibition of NO resulted in an increase in water excretion whether or not the increase in systolic BP was prevented by the coadministration of either quinapril or diltiazem. At the end of the experiment, LNAME-treated rats presented higher proteinuria than control rats (140 +/- 4 mg/24 hours v 21 +/- 1 mg/24 hours, P < .05). This elevated protein excretion was normalized by both antihypertensive drugs. None of the treatments was able to modify either natriuresis or plasma creatinine levels. Endothelium-dependent relaxations to acetylcholine (10(-12) to 10(-8) mol/L) were comparable in all groups. However, the vasoconstriction induced by either the continuous infusion of phenylephrine (10(-5) mol/L) or by a bolus of angiotensin II (1 nmol) was higher in the animals that received LNAME than in control ones. The antihypertensive therapy normalized the response to phenylephrine but not to angiotensin II. These data suggest that both quinapril and diltiazem are not only able to reduce BP elevation induced by the chronic administration of LNAME in rats, but also to prevent the renal damage and the hyperresponsiveness to phenylephrine induced by this NO synthesis inhibitor.
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PMID:Renal and vascular consequences of the chronic nitric oxide synthase inhibition. Effects of antihypertensive drugs. 893 32

This study was designed to determine whether the diabetic BioBreeding rat develops significant renal injury following long-term moderate to severe hyperglycaemia. Diabetic and control rats were followed from the onset of diabetes (2-4 months) to 18 months of age. Frank proteinuria and/or albuminuria were always absent. Glomerular filtration rate, measured by inulin clearance (ml min-1 (100 g body weight)-1), was significantly higher in diabetic rats than in controls at 10, 12 and 18 months of age. Advanced glycosylation end-product cross-links assessed by percentage solubility of tail tendon collagen were moderately increased in diabetic compared with control animals. Urinary excretion of advanced glycosylation end-products in unfractionated urine and in urine fractionated for low molecular mass peptides (< 10 kDa) was 11-fold greater in the diabetic rats than in the control group. Urinary excretion of nitric oxide metabolites (nmol NO2- and NO3- (24 h)-1) were significantly (P < 0.05) greater in diabetic rats than in controls after 8 months of age. Mild histopathology resembling human diabetic nephropathy, including increased mesangial volume and glomerular basement membrane thickness, was detected at 18 months of age. The findings of hyperfiltration and mild glomerular morphological changes in diabetic BioBreeding rats are similar to the abnormalities seen in stage 2 human diabetic nephropathy. We hypothesize that two factors which may contribute to the resistance or tolerance to renal injury in the BioBreeding diabetic rat are increased nitric oxide production and the decreased accumulation of advanced glycosylation end-products.
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PMID:Resistance to glomerular injury in the diabetic biobreeding rat. 896 13

The purpose of the present study was to examine renal functional changes caused by chronic blockade of nitric oxide (NO) synthesis in young rats. Two types of NO synthase inhibitor were used: NG-nitro-L-arginine methyl ester (L-NAME) as a non-selective inhibitor and aminoguanidine (AG) as a selective inhibitor of the inducible isoform. Oral administration of L-NAME (20-80 mg/dL of drinking water), not AG (400 mg/dL), for 4 weeks induced systemic hypertension in the treated rats. Both inhibitors caused a significant reduction in urinary excretion of NO2-/NO3-. Rats treated with L-NAME developed proteinuria and tubular enzymuria (high excretion of N-acetyl-beta-D-glucosaminidase) in a dose-dependent fashion, with normal serum levels of creatinine, albumin and cholesterol. Chronic AG administration did not alter the urinary levels of protein and N-acetyl-beta-D-glucosaminidase or serum laboratory values. Overall, these observations highlight the importance of the continuous generation of NO by the constitutive isoform in the control of vascular tone and the maintenance of renal glomerular and tubular function. Oral administration of L-NAME may serve as a model of chronic NO-deficient hypertension with renal injury in young rats.
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PMID:Renal functional measurements in young rats with chronic inhibition of nitric oxide synthase. 900 96

Diabetic nephropathy is preceded by 'hyperfiltration' mediated by dilatation of the afferent arterioles to the glomeruli by means of IGF-1, prostaglandins, bradykinin, nitric oxide and atrial natriuretic peptide, together with constriction of the efferent arterioles by local thromboxane A2. Raised glomerular intracapillary pressures might then contribute to glomerulosclerosis, but in any case there is permeability of the vascular endothelium. AGEPs and lipid peroxides can explain this. AGEPs, or simply intermittently high levels of glucose, also account for synthesis of extracellular matrix proteins that lead to thickening of the basement membrane and glomerulosclerosis. Another glucose product, glucosamine-6-phosphate, is formed when there is hexosamine flux along with insulin resistance in tissues, and is implicated in glomerulosclerosis, since it also stimulates TGF-beta transcription. In seeking to explain proteinuria, depletion of heparan sulphates from the endothelial cells and GBM is now established as a principal cause. In addition to a high glucose reducing the synthesis of heparan sulphates, it has now been shown that high glucose may depress the synthesis of heparin sulphate proteoglycan.
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PMID:How does hyperglycaemia predispose to diabetic nephropathy? 930 34

Remarkable advances have been made with prolonged antihypertensive therapy in reversing cardiovascular morbidity and mortality. Deaths from stroke have been reduced by 70% and from coronary heart disease by 35%. In contrast, endstage renal disease resulting from hypertension continues to increase. The explanations for this seeming paradox remain unresolved even though experimental models have demonstrated that certain antihypertensive agents may have beneficial renal and intrarenal hemodynamic effects; but reversal of the intrarenal pathological lesions have not been shown to improve. This discussion summarizes recent studies from our laboratory in aged (73- and 85-week-old) spontaneously hypertensive rats (SHR) with naturally occurring end-stage renal disease and in a model of aged SHR employing nitric oxide inhibition in younger, adult (20-week-old) SHR. Our findings demonstrated that the systemic and whole renal hemodynamics, intrarenal glomerular dynamics, proteinuria, and renal pathological lesions can be prevented or reversed with angiotensin-converting enzyme inhibition therapy but not with hydrochlorothiazide (at similar levels of arterial pressure reduction). The implications and possible mechanisms involved in the development of both naturally occurring and nitric oxide-exacerbated SHR are multifactorial, involving the endothelial nitric oxide system and its interaction with angiotensin II (and possibly bradykinin) among other factors. Moreover, these pathophysiological cellular mechanisms may be shared by the aging process as well as in naturally occurring spontaneous hypertension in the rat and, perhaps, in humans with essential hypertension. Thus, antihypertensive therapy seems to be specific in its ability to prevent and even reverse the pathophysiological derangements of renal involvement in hypertension. Thus, prevention and reversal of end-stage renal disease do not seem to require greater reduction of arterial pressure than with other target-organ involvement. However, they do require specific inhibition of the arteriolar and glomerular lesions produced by the disease.
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PMID:Arthus C. Corcoran Memorial Lecture. Influence of nitric oxide and angiotensin II on renal involvement in hypertension. 903

In diabetic nephropathy a major current concept for pathogenesis is increased collagen accumulation in the glomerulus by increased collagen synthesis and decreased degradation. In the present study, we tested the hypothesis whether arginine is able to influence kidney lipid peroxidation, glycoxidation, collagen accumulation, glucose-mediated cross-linking, hydroxy radical attack, protein oxidation, nitric oxide formation and albuminuria in the diabetic kk mouse. Ten diabetic kk mice were given arginine 50 mg/kg body weight, 10 diabetic kk mice were not treated and used as negative controls and 10 kk mice were kept as healthy controls. Our results show that oral administration of low-dose arginine reduces kidney collagen accumulation as reflected by kidney hydroxyproline, cross-linking as reflected by pentosidine, lipid peroxidation, glycoxidation as reflected by carboxymethyl lysine, kidney weight and albuminuria in the diabetic kk mouse. Albuminuria in untreated animals was closely correlated with lipid peroxidation. Our results in the spontaneously diabetic kk mouse representing type 2 diabetes mellitus therefore confirm and extend recent findings of collagen reduction by arginine in a different animal model. The mechanism of reducing proteinuria can be assigned to the blocking of lipid peroxidation products by L-arginine.
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PMID:Arginine reduces kidney collagen accumulation, cross-linking, lipid peroxidation, glycoxidation, kidney weight and albuminuria in the diabetic kk mouse. 904 44

Hypertensive complications are relatively common in pregnancy, particularly in the presence of preexisting renal disease. Although the pathogenesis of such complications is still unknown, recent animal studies have suggested that it may be related to impaired synthesis of nitric oxide (NO). Rats with adriamycin nephropathy develop a "preeclamptic-type" pregnant state characterized by elevated blood pressure, lack of hyperfiltration, and enhanced proteinuria. Preliminary studies with this model have implicated inadequate NO synthesis in the development of preeclamptic-like pregnancy. The aim of the present study was to confirm this hypothesis. Pregnant rats, both normal (PREG) and those with adriamycin nephropathy (AN-PREG), received 100 mg/L N omega-nitro-L-arginine methyl ester PO from the middle of gestation to term (day 11, term approximately 22 days). One group of AN-PREG rats received either L-arginine or D-arginine (2 g/L) from midpregnancy. At term, systolic pressure, mean arterial pressure, urinary metabolites of NO, creatinine clearance, and urinary protein were assessed. At term, compared with virgin rats with adriamycin nephropathy, untreated AN-PREG rats had increased systolic pressure, mean arterial pressure, and proteinuria (mean arterial pressure, 124 +/- 2.5 versus 99.7 +/- 1.6 mm Hg [P < .05]; proteinuria, 434 +/- 58 versus 216 +/- 63 mg/d [P < .05]). Creatinine clearance did not change (1.68 +/- 0.23 versus 1.35 +/- 0.09 mL/min, P = NS). In PREG rats, urinary metabolites of NO increased approximately threefold at term pregnancy compared with control. By contrast, in AN-PREG rats, excretion of urinary metabolites of NO increased only by approximately 1.7-fold (P < .01) versus PREG rats. With the exception of AN-PREG rats, inhibition of NO synthesis with N omega-nitro-L-arginine methyl ester enhanced blood pressure and decreased creatinine clearance but did not influence proteinuria. Excretion of urinary metabolites of NO was similarly inhibited in all rats. In AN-PREG rats, L-arginine normalized blood pressure (91 +/- 2.15 mm Hg) and lowered proteinuria partially but significantly. D-Arginine had no effect. In summary, AN-PREG rats are unable to adequately increase NO synthesis when physiologically required. Correction of this deficit by L-arginine treatment induced a significant clinical improvement.
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PMID:Pregnancy-induced hypertension in rats with adriamycin nephropathy is associated with an inadequate production of nitric oxide. 909 88

1. To investigate the role of nitric oxide (NO) in diabetic nephropathy the effect of nitric oxide synthase (NOS) inhibition by NG-nitro-L-arginine methyl ester (L-NAME) was observed in a streptozotocin diabetic spontaneously hypertensive rat (SHR) model. 2. Two groups of SHR (n = 8) with streptozotocin-induced diabetes were studied. One group was given L-NAME 5 mg/kg bodyweight per day in the drinking water for 8 weeks while both groups received daily subcutaneous injections of Ultratard insulin. Creatinine clearance, urinary protein excretion, urinary nitrate concentration and systolic blood pressure were measured at fortnightly intervals. Rats were killed at 8 weeks and plasma angiotensin II (AngII) was measured by radioimmunoassay. 3. Renal function (endogenous creatinine clearance) remained stable in both groups. In the L-NAME group, however, there was a progressive increase in proteinuria that was highly significant at 6 weeks (22.1 +/- 2.9 compared with 6.5 +/- 0.7 mg/ 24 h per 100 g in control SHR diabetic rats P < 0.001). 4. Systolic blood pressure was significantly elevated in the L-NAME group throughout the study compared with the control group. 5. Plasma AngII was significantly elevated in the L-NAME group compared with controls (42.8 +/- 10.3 vs 15.1 +/- 1.9 pmol/L, respectively; P < 0.05). 6. Activation of the renin-angiotensin system may account, at least in part, for the resulting vasoconstrictor activity with chronic nitric oxide depletion.
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PMID:Nitric oxide synthase inhibition in a spontaneously hypertensive rat model of diabetic nephropathy. 917 57


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