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)

In a rat model of glomerular immune injury induced by administration of anti-glomerular basement membrane antibody and resembling human rapidly progressive glomerulonephritis, we explored whether activation of inducible nitric oxide synthase (iNOS) regulates synthesis of eicosanoids originating from cyclooxygenation or lipoxygenation of arachidonic acid. At early stages (24 hr) of injury, inhibition of iNOS using the selective inhibitor L-N6-(1-iminoethyl) lysine (L-NIL) at doses sufficient to reduce urinary excretion of nitrate/nitrite, reduced glomerular synthesis of the prostaglandins PGE2 and PGI2, but had no effect on that of thromboxane A2 (TxA2). The syntheses of 5-hydroxyeicosatetraenoic acid (HETE), 15-HETE and leukotriene B4 (LTB4) were also reduced. That of 12-HETE remained unchanged. We also explored the effect of arachidonate cyclooxygenation and lipoxygenation eicosanoids on iNOS expression. Administration of the cyclooxygenase (COX) inhibitor, indomethacin, at doses sufficient to inhibit glomerular prostaglandin synthesis, increased iNOS mRNA levels in glomeruli. Administration of the 5-lipoxygenase (5-LO) inhibitor, MK-0591, at doses sufficient to inhibit glomerular LTB4 synthesis also increased iNOS mRNA. The effect of 5-LO inhibition on iNOS expression was more pronounced than that of COX inhibition. In nephritic animals given the iNOS inhibitor, L-NIL, or indomethacin proteinuria worsened. In those given the 5-lipoxygenase inhibitor there was no change in urine protein excretion. These observations point to regulatory interactions between the arachidonic acid and the L-arginine: NO pathways in glomerulonephritis. These interactions are of importance in considering antiinflammatory strategies based on inhibition of iNOS or of specific eicosanoids.
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PMID:Regulatory interactions between inducible nitric oxide synthase and eicosanoids in glomerular immune injury. 950 10

Although a lot of animal models of proteinuria have been established, proposals for the mechanisms of proteinuria are still controversial. In this work, during an 18-day trial, mice injected with a single dose of adriamycin (AD) rapidly showed combined glomerular albuminuria and immunoglobulinuria, progressively elevated levels of nitrite/nitrate in urine, hypercholesterolemia, abnormal renal function, segmentally or globally glomerular hyalinosis/sclerosis associated with tubular atrophy, enhanced glomerular deposition of immunoglobulins and fibrinogen, augmented expression of matrix components in the whole glomerular tuft, and loss of glomerular negative charge property. These laboratory and pathological features are comparatively similar to those of human focal segmental glomerulosclerosis in the advanced state. Juxtamedullary glomeruli appear to be more susceptible to the AD-related nephrotoxicity than those in the superficial renal cortex. A change in size-dependent glomerular permselectivity may precede a charge-dependent defect in glomeruli in this mouse model of proteinuria. Data in this study confirm the hypothesis of glomerular hyperfiltration involved in the pathogenesis of this chronic glomerulopathy associated with proteinuria in mice. In addition, nitric oxide may play a crucial role in the progression of the chronic glomerulopathy model.
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PMID:Experimental focal segmental glomerulosclerosis in mice. 957 71

Normal pregnancy is characterized by a significant reduction in total peripheral vascular resistance and decreased pressor responsiveness to vasodilator agents. This review will consider whether nitric oxide (NO) contributes to these changes, and whether a deficiency of NO produces a preeclampsia like syndrome. The biosynthesis of NO increases in pregnant animals, as assessed by the raised plasma concentration, urinary excretion and metabolic production rate of guanosine 3',5'-cyclic monophosphate (cGMP), the second messenger of NO. In addition, urinary excretion of nitrate, the stable metabolites of NO, increases during pregnancy, paralleling the rise in cGMP. Several studies provide convincing evidence indicating that expression and activity of different NO synthases (NOS) are increased in gravid animals. Acute blockade of NOS causes a dose response increase in blood pressure and reverses the blunted vasopressor response to vasoconstrictor agents. Long-term NOS inhibition produces a pre-eclampsia like syndrome, characterized by maternal hypertension, proteinuria, thrombocytopenia, and renal damage, and lower litter size and fetal weight. Both acute and chronic responses are reduced when L-arginine, the substrate for NOS, is administered in high doses, indicating that these changes are specific to NO inhibition. In conclusion, present data suggest that a disturbance in NO release may contribute to the pathogenesis of pre-eclampsia.
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PMID:Role of nitric oxide in maternal hemodynamics and hormonal changes in pregnant rats. 983 May 12

We used streptozotocin (STZ) to induce the animal model of diabetes mellitus in rats. On the 7th and 14th days of induction, kidney disorder, the levels of NO3- in plasma and tissue homogenate in different periods were observed. The NO3- levels in relation to the application of L-arginine (L-Arg) were also noted. The results showed that the kidney weight/body weight ratio significantly increased in different periods (P < 0.05). On the 7th day profuse proteinuria appeared and it markedly increased on the 14th day: creatinine clearance rate (Ccr) significantly raised, too (P < 0.005). The NO3- levels in plasma and tissue homogenate were getting higher with time. The level of NO3- significantly increased after L-Arg was perfused. It indicated that kidney disorder was present at the early stage of diabetes, and the raised Ccr indirectly indicated the increase of glomerular filtration rate. These suggest that NO3- and L-Arg may be important mediums which have effects of hyperfiltration and hyperperfusion of glomerulus.
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PMID:[L-arginine and nitric oxide have effects on glomerulus hyperperfusion of early diabetic rats]. 1068 27

Oxidative products of nitric oxide, serum nitrates and nitrites were estimated in 50 primigravidas with preeclampsia and in 50 gestation and age-matched normotensive primigravidas. Thirty three (66%) of these women had mild preeclampsia and 17 (34%) had severe preeclampsia. Serum nitrate and nitrite levels were significantly higher in preeclamptic women (nitrates - 15 +/- 1.17; nitrites - 11.82 +/- 1.16 micromol/L) than in the normotensive pregnant women (nitrates 11.82 +/- 1.16; nitrites - 5.08 +/- 0.47 micromol/L, p < 0.001). In preeclamptic women, serum nitrate and nitrite levels correlated with the severity of the disease (mild preeclampsia nitrate - 14.46 +/- 1.98; nitrite 6.21 +/- 0.84 micromol/L, severe preeclampsia nitrate - 16.65 +/- 3.64; Nitrite - 6.87 +/- 1.56 micromol/L). In preeclampsia there was significant positive correlation between nitrate and nitrite levels and diastolic blood pressure and proteinuria.
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PMID:Estimation of oxidative products of nitric oxide (nitrates, nitrites) in preeclampsia. 1068 70

Puromycin aminonucleoside (PAN) administration in rats produces an experimental model of nephrotic syndrome characterized by glomerular epithelial cell injury and proteinuria. The purpose of this study was to examine the role of nitric oxide (NO) in this model of minimal change glomerular disease. Aminoguanidine (AG) was used to inhibit inducible nitric oxide synthase (iNOS). Sprague-Dawley rats were divided into Control (N = 9), PAN (N = 14), AG (N = 2), and PAN + AG (N = 12) treatment groups. Control animals received saline (i.v. ), PAN animals received PAN (75 mg/kg, i.v.), and PAN + AG animals received PAN plus AG (50 mg/kg, i.p., twice daily). AG animals received a saline injection (i.v.) on day 0 in the place of PAN and then AG on the same schedule as the PAN + AG group. Animals were kept in metabolic cages, and urinary protein excretion and nitrite (NO(2)(-)) excretion were measured daily. PAN administration increased urinary NO(2)(-) excretion by day 2, and levels remained elevated through day 7. AG prevented this PAN-induced increase in urinary NO(2)(-) excretion. Plasma nitrate (NO(3)(-)) and NO(2)(-) (NOx) concentrations were also increased in the PAN and PAN + AG groups. iNOS protein expression was not detected in either the glomeruli or the cortex at day 7. Proteinuria developed in PAN animals on day 4 and increased steadily through day 7. PAN + AG animals showed a pattern similar to that of the PAN group. These results indicated that in contrast to models of proliferative glomerulonephritis, NO formation during PAN-induced nephrotic syndrome is increased but does not participate in the development of glomerular injury as measured by proteinuria.
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PMID:Lack of a role for inducible nitric oxide synthase in an experimental model of nephrotic syndrome. 1080 55

Cationic colloidal gold (CCG), a polycationic histochemical probe, was used to analyze the distribution of glomerular basement membrane (GBM) polyanions, mainly heparan sulfate proteoglycan in spontaneous hypertensive rats (SHR) with or without salt loading and antihypertensive treatment with propranolol. The changes of mean GBM width and anionic sites distribution were assessed by electron microscopy. Plasma and urinary nitrates (NO(x)) were measured by nitrite (NO2) + nitrate (NO3), stable metabolites of NO. SHR had decreased NO production and increased GBM width (27%) compared with the control Wistar-Kyoto (WKY) rats. The chronic high dietary salt intake resulted in a significant increase in blood pressure, proteinuria, and renal function in the SHR rats. The chronic high salt dietary intake resulted in a decrease in NO in the WKY and a further reduction in NO production in the SHR. The GBM anionic sites count was similar in the SHR and WKY nonsalt-loaded groups, 13.5 +/- 0.5 and 12.8 +/- 0.4 CCG counts/microm GBM, respectively, but significantly lower in both salt-loaded SHR and WKY, 9.9 +/- 0.55 (P < .01) and 9.6 +/- 0.55 (P < .01) CCG counts/microm GBM, respectively. Antihypertensive treatment with propranolol in the salt-loaded SHR group resulted in lower blood pressure, a further decrease in NO production, but no significant changes in GBM width and anionic sites count. It is concluded that chronic high salt intake may be deleterious to the permselectivity of the GBM. A low NO production state that results from chronic salt loading in already hypertensive rats will result in more severe organ (renal) damage, most probably by the addition of the loss of GBM permselectivity to the existing pathomorphologic changes.
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PMID:Glomerular basement membrane polyanion distribution and nitric oxide in spontaneous hypertensive rats: effects of salt loading and antihypertensive therapy with propranolol. 1093 77

To elucidate the role of nitric oxide (NO) and renin-angiotensin system (RAS) in the development of salt-sensitive hypertension, we investigated the pressor responses and renal histologic changes after long-term inhibition of endogenous NO synthesis in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats under salt-re-stricted conditions that exaggerate RAS activation. Male DS and DR rats (6 weeks old) were fed with a low-salt (0.3%) diet for 5 weeks. NG-nitro-L-arginine (L-NA; dissolved in 60 mg/L deionized water), an arginine analogue acting as a NO-inhibitor, was also administered for 5 weeks. L-NA administration induced a gradual increase in systolic blood pressure (SBP) in both strains, and the pressor response in DS rats was apparently more enhanced relative to that in DR rats. Urinary nitrate plus nitrite (u-NOx) excretion was decreased by L-NA, with a significant negative correlation between SBP and u-NOx excretion in DS rats but not in DR rats. Plasma renin activity and urinary aldosterone level were significantly increased in L-NA-treated DS rats on week 5. Marked histologic changes with glomerular sclerosis and increased proteinuria and urinary N-acetyl-beta-glucosaminidase excretion were found in L-NA-treated DS rats but not DR rats. Competitive RT-PCR of mRNA extracted from the glomeruli revealed that angiotensin II type 1 receptor (AT1R) mRNA level was significantly lower in DS rats than in DR rats at week 2, and that L-NA administration significantly reduced glomerular AT1R level of DS rats at week 5, possibly because of downregulation. Our results showed that, even under sodium restriction, the pressor response and renal injury induced by chronic NO inhibition were markedly more enhanced in DS rats than in DR rats, which indicates that depletion of NO participates in both the development of hypertension and glomerular injury in DS rats through a potential activation of RAS irrespective of sodium loading. These data suggest that endogenous NO is an essential determinant of salt-sensitive hypertension in DS rats.
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PMID:The role of nitric oxide and the renin-angiotensin system in salt-restricted Dahl rats. 1128 Dec 41

Anew model of thrombotic microangiopathy (TMA) was previously developed, and it was demonstrated that endothelial nitric oxide (NO) synthase (NOS) is upregulated in glomeruli in this model. It was hypothesized that the synthesis of NO, a potent vasodilator and platelet inhibitory factor, is induced as a defense mechanism. The goal of this study was to clarify the role of NO in this model. Ex vivo experiments using Western blotting and functional assays demonstrated upregulation of endothelial NOS in isolated glomeruli from TMA rats. In in vivo experiments, five groups of rats were studied, including rats with TMA treated with vehicle, N(G)-nitro-L-arginine methyl ester (L-NAME) (a NOS inhibitor), or L-N(6)-(1-iminoethyl)lysine (L-NIL) (a specific inducible NOS inhibitor) and normal control rats treated with vehicle or L-NAME. Blood urea nitrogen levels, BP, urinary nitrate/nitrite excretion, and proteinuria were measured. Histologic assessments using periodic acid-Schiff staining and immunohistologic studies with markers for endothelium, platelets, fibrin, cell proliferation, and apoptosis were also performed. L-NAME inhibition of NO synthesis in rats with TMA resulted in more severe glomerular and tubulointerstitial injury, which was accompanied by thrombus formation and a marked loss of endothelial cells, with more apoptotic cells. These changes were associated with severe renal function deterioration. In contrast, these features were less pronounced in the vehicle- or L-NIL-treated rats with TMA and were absent in the control animals. In conclusion, inhibition of NO production in this model of TMA markedly exacerbated renal injury. The absence of effects with L-NIL treatment suggests a minor role for inducible NOS in this model. These results suggest that production of NO, most likely by endothelial cells, is an important protective mechanism in TMA.
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PMID:Protective role of nitric oxide in a model of thrombotic microangiopathy in rats. 1156 7

In idiopathic calcium urolithiasis the relationships between oxypurines, accompanying proteins and glucose in urine and plasma, and the associated metabolic activity (MA) are unknown. To establish whether MA is related to these parameters and to calcium oxalate crystallization, or whether it reflects a reaction of metabolism to systemic insults was the major goal of the work. One hundred fifty one males were studied in three trials: trial 1 (n=130 patients) and trial 2 (n=24 patients) were cross-sectional; trial 3 included 11 patients and 14 controls). Mean age was 46 years (trials 1 and 2) and 29 years (trial 3). In trial 1 the stratification was based on the median urinary oxypurine excretion, in trial 2 on the median plasma oxypurine concentration (below or above: Low and High subgroups). No dietary restrictions were imposed, but standardized ambulatory laboratory testing was carried out. MA was quantitated by a score. Established analytical methods were used, except for oxypurine measurement which was done by high performance liquid chromatography. Patients with kidney stones tended to be overweight (body mass index >25 kg/(m)2) and to have fasting hyperglycemia. In trial 1 severe oxypurinuria, and especially severe xanthinuria, was associated with an increase in urinary pH, creatinine clearance, proteins, uric acid, malonedialdehyde (indicator of lipid peroxidation), systolic blood pressure, and with a decrease in plasma uric acid (synonymous with a decrease of antioxidant capacity). Tubular reabsorption of proteins and stone-forming substances was diminished but MA remained unchanged despite slightly increased calcium oxalate crystal growth. In trial 2 high adenosine and xanthine coincided with elevated systolic and diastolic blood pressure, high uric acid with high urinary malonedialdehyde, high summed oxypurines minus uric acid with an increase of diastolic blood pressure, glycemia and MA; urinary nitrate (indicator of systemic vasodilation) was unchanged. In trial 3 patients' oxypurinemia and proteinuria were normal, but body mass index, glycemia and insulinemia were increased. Urinary total protein, albumin and non-albumin proteins were positively predicted (multivariate regression analysis) by urinary xanthine, glucose and pH (trial 1); MA was positively (trial 3) or negatively (trial 2) predicted by urinary total protein. In calcium urolithiasis, a disorder of affluence, 1) oxypurinuria and proteinuria and oxypurinemia and MA appear causally linked, presumably via oxidant/antioxidant imbalance-induced renal tissue damage; 2) urinary proteins may act as inhibitors or promoters of stone-forming processes; 3) a stone-initiating role of impaired vasodilatation is conjectural; 4) overweight, obesity, mild glucosuria and hyperdynamic blood circulation are regular signs.
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PMID:Oxypurines, protein, glucose and the functional state of blood vasculature are markers of renal calcium stone-forming processes? Observations in men with idiopathic recurrent calcium urolithiasis. 1200 17


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