atrial-natriuretic-factor and Proteinuria

Oedema formation in the nephrotic syndrome is primarily due to tubular sodium retention. The pathogenetic role of alpha atrial natriuretic peptide (ANP), a hormonal promoter of natriuresis is unknown.. In 31 patients (aged 35+/-11 years) with nephrotic syndrome and histopathological evidence of primary glomerulonephritis, we investigated plasma ANP concentration and its influence on renal haemodynamics, natriuresis, and proteinuria (total protein, albumin, IgG excretion). Patients with a compensated treated form of nephrotic syndrome due to primary glomerulonephritis were included in the study. Serum creatinine levels were <=1.4 mg/dl. Diuretic medication was discontinued at least 24 h before the investigation was started. Patients were randomly assigned to ANP infusion (0.005 microg/kg*min; group II, n=15) or received placebo (group III, n=16). Ten healthy subjects (group I) served as normal controls.. In normal subjects (group I), ANP caused an increase in natriuresis from 14.5+/-4.2 mmol/h to 26.4+/-11.1 mmol/h (P<0.01). In patients with nephrotic syndrome (group II), baseline sodium excretion of 10.5+/-6.0 mmol/h was increased to 19.6+/-14.8 mmol/h with ANP infusion (P<0.01). No changes were seen in the placebo group III. The absolute increase in ANP induced natriuresis was not significantly different between group I and II. However, plasma ANP levels were significantly higher in patients with nephrotic syndrome (166+/-87 pg/ml vs. 74+/-21 pg/ml, P<0.05) and also reached higher levels after ANP infusion (P<0.01). Therefore, natriuresis was significantly reduced when circulating ANP levels were taken into account (P<0.05). ANP administration resulted in an increase of total protein excretion in patients with the nephrotic syndrome (group II, from 219+/-277 mg/h to 264+/-268 mg/h). Albumin elimination rose from 128+/-151 mg/h to 167+/-170 mg/h (P<0.05) and IgG excretion from 4.91+/-6.67 mg/h to 9.27+/-10.78 mg/h (P<0.05). Healthy subjects also showed a small but significant increase in albuminuria (48+/-38%, P<0.05). Low-dose ANP infusion did not, however, induce any significant alteration in GFR, ERPF and blood pressure.. ANP plasma concentrations in the steady state are elevated in patients with the nephrotic syndrome. The natriuretic effect of ANP is reduced when referring to circulating ANP plasma levels. Elevated ANP levels enhance urinary protein excretion in the nephrotic syndrome. This is not due to modulation of GFR or FF, but is most probably attributable to increased glomerular permeability.

Topics: Adult; Atrial Natriuretic Factor; Blood Volume; Cyclic GMP; Female; Hemodynamics; Humans; Male; Natriuresis; Nephrotic Syndrome; Proteinuria; Renal Circulation; Serum Albumin; Sodium

Synthetic human atrial natriuretic peptide (ANP) (102-126) 0.01 microgram/kg per minute or vehicle was intravenously infused for 2 h in 10 patients with insulin-dependent diabetes mellitus and microalbuminuria (albumin excretion, 20 to 200 micrograms/min) and in 10 healthy subjects. In the diabetic group, the immunoglobulin G clearance was higher, but both size index and charge index as calculated from albumin and immunoglobulin clearances were equal compared with normal values. The fractional clearances of small dextrans (< 3.6 nm) were lower in diabetics, which was compatible with a depressed hydraulic permeability (Kf). During ANP infusion, the excretion of albumin and immunoglobulin G increased in the diabetic subjects (189 +/- 12 to 521 +/- 84 and 7.1 +/- 3.5 to 21 +/- 8.1 micrograms/min, respectively; both P < 0.05) only. In the diabetics, the clearance of dextrans > 54 A increased and our calculations indicated an increase in "shut-flow" (omega o). The transcapillary escape rate of albumin, which was elevated in the diabetics at baseline, increased in the diabetic group only. Thus, ANP uncovers altered size selectivity of the filtration barrier in a phase that is otherwise characterized by charge-selective changes only. Moreover, the increased susceptibility of the glomerular capillaries in diabetics to ANP seems to be part of a more generalized capillary abnormality, because ANP also increases the transcapillary escape of albumin.

Topics: Adult; Albuminuria; Atrial Natriuretic Factor; Basement Membrane; Capillary Permeability; Dextrans; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Humans; Immunoglobulin G; Kidney Glomerulus; Male; Middle Aged; Models, Biological; Natriuresis; Peptide Fragments; Proteins; Proteinuria; Renal Circulation

1. To examine whether or not atrial natriuretic peptide-induced proteinuria simply results from increases in urine flow or glomerular filtration rate, we infused dopamine (1 microgram min-1 kg-1) and alpha-human atrial natriuretic peptide (0.025 microgram min-1 kg-1) into nine patients with chronic glomerulonephritis and nine essential hypertensive patients without renal damage, and compared the effects of the two agents on renal function and urinary protein excretion. 2. In patients with chronic glomerulonephritis, dopamine infusion significantly increased urinary sodium excretion (+59%), renal blood flow (+20%) and creatinine clearance (+14%). However, urinary protein excretion was not changed. Addition of atrial natriuretic peptide to the dopamine infusion further increased urinary sodium excretion and maintained creatinine clearance at the same level. In contrast to the infusion of dopamine alone, atrial natriuretic peptide markedly increased urinary protein excretion (77 versus 229 mg min-1 m2, P less than 0.02). Furthermore, the addition of atrial natriuretic peptide elevated the urinary protein/creatinine ratio (1.55 versus 5.35, P less than 0.05), while dopamine alone did not (1.55 versus 1.45, not significant). 3. In essential hypertensive patients, dopamine and dopamine plus ANP showed renal effects similar to those of chronic glomerulonephritis; however, the urinary excretion of protein was not changed significantly. 4. These results suggest that atrial natriuretic peptide may increase urinary protein excretion mainly by increasing the permeability of the damaged glomeruli to protein rather than by simply increasing urine flow or glomerular filtration. Possible mechanisms underlying the proteinuria-increasing effects of atrial natriuretic peptide are discussed.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Cyclic GMP; Dopamine; Glomerular Filtration Rate; Glomerulonephritis; Heart Rate; Humans; Hypertension; Kidney; Middle Aged; Proteinuria; Urination

Glomerular diseases (GD) lead to a variety of disorders of the vascular and the total body water volumes. Various pathomechanisms, including vascular underfill and overfill, have been suggested to explain these disturbances. Accordingly, the circulating renin-angiotensin-aldosterone system (cRAAS) is expected to be activated as either a cause or a result of these fluid disorders. The aim of this study was to characterize the activity of the cRAAS in dogs with GD and to evaluate its relationship with the vascular volume status. In a prospective study, we evaluated the plasma renin activity and the serum aldosterone concentration in 15 dogs with GD. Their fluid volume status was estimated with clinical variables reflecting volemia and hydration, echocardiographic volume assessment, N-terminal pro B-type natriuretic peptide, blood urea nitrogen:creatinine ratio, and the urinary fractional excretion of sodium. Ten dogs with chronic kidney disease (CKD) with matching degree of azotemia were recruited as controls. The activity of the cRAAS was low in 10 dogs, normal in 3 dogs, high in 1 dog and equivocal (high renin-low aldosterone) in 1 dog with GD. These dogs had a lower cRAAS activity than dogs with CKD (p = 0.01). The clinical evaluation showed 8 hypovolemic and 7 non-hypovolemic dogs; 3 dehydrated, 9 euhydrated and 3 overhydrated dogs. The cRAAS activity was not different between hypovolemic and non-hypovolemic dogs. The down-regulated cRAAS without obvious association with the clinical volume status of these dogs with GD, suggests different mechanisms of fluid volume dysregulation in dogs with GD than previously assumed. This finding however should be confirmed in a focused larger scale study, as it may influence the use of cRAAS blockers as part of the standard therapy of GD in dogs.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Azotemia; Blood Urea Nitrogen; Dog Diseases; Dogs; Down-Regulation; Female; Glomerulonephritis; Male; Prospective Studies; Protein Precursors; Proteinuria; Renal Insufficiency, Chronic; Renin

Glomerular podocytes play a key role in proteinuric diseases. Accumulating evidence suggests that cGMP signaling has podocyte protective effects. The major source of cGMP generation in podocytes is natriuretic peptides. The natriuretic peptide clearance receptor (NPRC) binds and degrades natriuretic peptides. As a result, NPRC inhibits natriuretic peptide-induced cGMP generation. To enhance cGMP generation in podocytes, we blocked natriuretic peptide clearance using the specific NPRC ligand ANP(4-23). We then studied the effects of NPRC blockade in both cultured podocytes and in a mouse transgenic (TG) model of focal segmental glomerulosclerosis (FSGS) created in our laboratory. In this model, a single dose of the podocyte toxin puromycin aminonucleoside (PAN) causes robust albuminuria in TG mice, but only mild disease in non-TG animals. We found that natriuretic peptides protected cultured podocytes from PAN-induced apoptosis, and that ANP(4-23) enhanced natriuretic peptide-induced cGMP generation in vivo. PAN-induced heavy proteinuria in vehicle-treated TG mice, and this increase in albuminuria was reduced by treatment with ANP(4-23). Treatment with ANP(4-23) also reduced the number of mice with glomerular injury and enhanced urinary cGMP excretion, but these differences were not statistically significant. Systolic BP was similar in vehicle and ANP(4-23)-treated mice. These data suggest that: 1. Pharmacologic blockade of NPRC may be useful for treating glomerular diseases such as FSGS, and 2. Treatment outcomes might be improved by optimizing NPRC blockade to inhibit natriuretic peptide clearance more effectively.

Topics: Animals; Apoptosis; Atrial Natriuretic Factor; Cell Line; Cyclic GMP; Female; Glomerulosclerosis, Focal Segmental; Male; Mice; Natriuretic Peptides; Peptide Fragments; Podocytes; Proteinuria; Receptors, Atrial Natriuretic Factor

The combination of AT1 blocker/neutroendopeptidase neprilysin inhibition (ARNi) represents an interesting approach to reduce cardiovascular risk in hypertension. We assessed the efficacy of ARNi, compared with angiotensin II type 1 receptor blockade alone, on blood pressure (BP) and on protection from target organ damage development in the stroke-prone spontaneously hypertensive rat (SHRSP).. In high-salt fed SHRSP, we assessed plasma and tissue natriuretic peptides, urinary volume, BP and body weight over a short-term treatment (6 weeks) with either ARNi (sacubitril/valsartan 68 mg/kg per day) or valsartan (30 mg/kg per day), protection from stroke and renal damage (as documented by proteinuria) over 4 months of treatment with either sacubitril/valsartan or valsartan; the ability of either treatment to reduce progression of cerebrovascular and renal damage after 2 weeks of high-salt diet.. Higher levels of plasma and tissue atrial natriuretic peptide, of urinary cyclic guanosine 3'5'monophosphate and urine volumes, along with lower BP levels, were found upon sacubitril/valsartan as compared with valsartan over the short-term treatment. Sacubitril/valsartan caused a significant reduction of both BP and proteinuria levels and complete prevention of stroke over the long-term treatment. Once organ damage was established, a significant delay of its progression was observed with sacubitril/valsartan.. The dual angiotensin II type 1 receptor/neutroendopeptidase inhibition significantly increased atrial natriuretic peptide level and reduced BP. Complete prevention of stroke was achieved in this model. The ability of sacubitril/valsartan to reduce organ damage progression was superior to that of valsartan alone. ARNi may represent a highly effective therapeutic agent to protect from target organ damage development in hypertension.

Topics: Aminobutyrates; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Biphenyl Compounds; Blood Pressure; Cyclic GMP; Drug Combinations; Hypertension; Male; Neprilysin; Proteinuria; Rats; Rats, Inbred SHR; Stroke; Tetrazoles; Valsartan

Angiotensin-converting enzyme (ACE) inhibitors ameliorate the progression of renal disease. In combination with vitamin D receptor activators, they provide additional benefits. In the present study, uremic (U) rats were treated as follows: U+vehicle (UC), U+enalapril (UE; 25 mg/l in drinking water), U+paricalcitol (UP; 0.8 μg/kg ip, 3 × wk), or U+enalapril+paricalcitol (UEP). Despite hypertension in UP rats, proteinuria decreased by 32% vs. UC rats. Enalapril alone, or in combination with paricalcitol, further decreased proteinuria (≈70%). Glomerulosclerosis and interstitial infiltration increased in UC rats. Paricalcitol and enalapril inhibited this. The increase in cardiac atrial natriuretic peptide (ANP) seen in UC rats was significantly decreased by paricalcitol. Enalapril produced a more dramatic reduction in ANP. Renal oxidative stress plays a critical role in inflammation and progression of sclerosis. The marked increase in p22(phox), a subunit of NADPH oxidase, and decrease in endothelial nitric oxide synthase were inhibited in all treated groups. Cotreatment with both compounds inhibited the uremia-induced increase in proinflammatory inducible nitric oxide synthase (iNOS) and glutathione peroxidase activity better than either compound alone. Glutathione reductase was also increased in UE and UP rats vs. UC. Kidney 4-hydroxynonenal was significantly increased in the UC group compared with the normal group. Combined treatment with both compounds significantly blunted this increase, P < 0.05, while either compound alone had no effect. Additionally, the expression of Mn-SOD was increased and CuZn-SOD decreased by uremia. This was ameliorated in all treatment groups. Cotreatment with enalapril and paricalcitol had an additive effect in increasing CuZn-SOD expression. In conclusion, like enalapril, paricalcitol alone can improve proteinuria, glomerulosclerosis, and interstitial infiltration and reduce renal oxidative stress. The effects of paricalcitol may be amplified when an ACE inhibitor is added since cotreatment with both compounds seems to have an additive effect on ameliorating uremia-induced changes in iNOS and CuZn-SOD expression, peroxidase activity, and renal histomorphometry.

Topics: Aldehydes; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Enalapril; Ergocalciferols; Female; Glomerulonephritis; Kidney; NADPH Oxidases; Nitric Oxide Synthase Type II; Oxidative Stress; Proteinuria; Rats; Receptors, Calcitriol; Superoxide Dismutase; Uremia

Patients with proteinuric kidney diseases often have symptoms of salt and water retention. It has been hypothesized that dysregulated sodium absorption is due to increased proteolytic cleavage of epithelial sodium channels (ENaCs) and increased Na,K-ATPase expression. Microarray analysis identified a reduction in kidney corin mRNA expression in rat models of puromycin aminonucleoside-induced nephrotic syndrome and acute anti-Thy1 glomerulonephritis (GN). As atrial natriuretic peptide (ANP) resistance is a mechanism accounting for volume retention, we analyzed the renal expression and function of corin; a type II transmembrane serine protease that converts pro-ANP to active ANP. Immunohistochemical analysis found that corin colocalized with ANP. The nephrotic and glomerulonephritic models exhibited concomitant increased pro-ANP and decreased ANP protein levels in the kidney consistent with low amounts of corin. Importantly, kidneys from corin knockout mice had increased amounts of renal β-ENaC and its activators, phosphodiesterase (PDE) 5 and protein kinase G II, when compared to wild-type mice. A similar expression profile was also found in cell culture suggesting the increase in PDE5 and kinase G II could account for the increase in β-ENaC seen in nephrotic syndrome and GN. Thus, we suggest that corin might be involved in the salt retention seen in glomerular diseases.

Topics: Animals; Aquaporin 2; Atrial Natriuretic Factor; Cyclic AMP; Epithelial Sodium Channels; Glomerulonephritis; HEK293 Cells; Humans; Kidney; Male; Mice; Nephrotic Syndrome; Proteinuria; Rats; Rats, Wistar; Serine Endopeptidases; Sodium

The interplay between the heart and the kidneys has received widespread attention in recent years. A novel five-class definition of cardiorenal syndromes has been proposed. The ability of two markers of cardiac dysfunction to predict progression of primary kidney disease, described by Dieplinger and his co-workers, highlights the prognostic importance of the chronic cardiorenal (types 2 and 4) syndromes.

Topics: Adrenomedullin; Age Factors; Atrial Natriuretic Factor; Biomarkers; Creatinine; Disease Progression; Glomerular Filtration Rate; Heart; Heart Failure; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Proteinuria; Sex Factors

Inhibition of the renin angiotensin aldosterone system (RAAS) produces protective effects on cardio-renal injury in type 2 diabetes. Vasopeptidase inhibitors (VPI) represent a new pharmacological tool, acting by simultaneous inhibition of the RAAS and neutral endopeptidase. We examined the effects of chronic VPI on renal function and morphology in experimental type 2 diabetes as compared to angiotensin converting enzyme inhibition (ACE-I). Zucker diabetic fatty rats aged 13 weeks were treated with either VPI (AVE7688, ZDF-VPI, n = 8) or ACE-I (Ramipril, ZDF-ACE-I, n = 7) or placebo (ZDF, n = 8). Heterozygous rats served as non-diabetic controls (Ctr, n = 8). Both treatments led to a similar decrease in blood pressure. After 10 weeks of treatment, ZDF developed marked albuminuria. The latter was significantly attenuated in ZDF-VPI as compared to ZDF and ZDF-ACE-I. Renal histology revealed a significant expansion in the glomerular tuft area in all ZDF groups. However, expression of glomerular desmin, which has been recognized as a sensitive marker of early podocyte damage, was significantly increased in ZDF as compared to Ctr. Desmin was reduced in ZDF-VPI but not in animals treated with ACE-I. There was a correlation between albumin excretion and desmin-positive glomerular area. In experimental type 2 diabetes, albuminuria correlates to podocyte damage. These hallmarks of diabetic nephropathy are attenuated by VPI to a greater extent than by ACE-I alone. These findings suggest that podocyte damage is an early critical step in the progression of diabetic nephropathy, and that VPI is a promising pharmacological tool in the treatment of diabetic renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Diabetes Mellitus, Experimental; Heterocyclic Compounds, 3-Ring; Male; Microscopy, Polarization; Neprilysin; Podocytes; Protease Inhibitors; Proteinuria; Ramipril; Rats; Rats, Zucker; Renin-Angiotensin System; Triglycerides; Weight Gain

Atrial natriuretic peptide (ANP) is a cardiac hormone that regulates blood pressure. In cardiomyocytes, the hormone is synthesized as a precursor, proatrial natriuretic peptide (pro-ANP), which is proteolytically converted to active ANP. Corin is a cardiac transmembrane serine protease that has been shown to process pro-ANP in vitro, but its physiological importance had not been established. Here, we show that corin-deficient (Cor-/-) mice develop normally during embryogenesis and survive to postnatal life. Cor-/- mice have elevated levels of pro-ANP but no detectable levels of ANP as compared with WT littermates. Infusion of an active recombinant soluble corin transiently restores pro-ANP conversion, resulting in the release of circulating biologically active ANP. Using radiotelemetry to assess blood pressure, we find that Cor-/- mice have spontaneous hypertension as compared with WT mice, and it is enhanced after dietary salt loading. Pregnant Cor-/- mice demonstrate late-gestation proteinuria and enhanced high blood pressure during pregnancy. In addition, Cor-/- mice exhibit cardiac hypertrophy resulting in a mild decline in cardiac function later in life. Thus, our data establish corin as the physiological pro-ANP convertase and indicate that corin deficiency may contribute to hypertensive heart disease.

Topics: Animals; Atrial Natriuretic Factor; Cardiomegaly; Embryonic Development; Female; Hypertension; Male; Mice; Pregnancy; Pregnancy Complications; Protein Precursors; Proteinuria; Serine Endopeptidases; Sodium Chloride

Data regarding the effectiveness of chronic exercise training in improving survival in patients with congestive heart failure (CHF) are inconclusive. Therefore, we conducted a study to determine the effect of exercise training on survival in a well-defined animal model of heart failure (HF), using the lean male spontaneously hypertensive HF (SHHF) rat. In this model, animals typically present with decompensated, dilated HF between approximately 18 and 23 mo of age. SHHF rats were assigned to sedentary or exercise-trained groups at 9 and 16 mo of age. Exercise training consisted of 6 mo of low-intensity treadmill running. Exercise training delayed the onset of overt HF and improved survival (P < 0.01), independent of any effects on the hypertensive status of the rats. Training delayed the myosin heavy chain (MyHC) isoform shift from alpha- to beta-MyHC that was seen in sedentary animals that developed HF. Exercise was associated with a concurrent increase in cardiomyocyte length (approximately 6%), width, and area and prevented the increase in the length-to-width ratio seen in sedentary animals in HF. The increases in proteinuria, plasma atrial natriuretic peptide, and serum leptin levels observed in rats with HF were suppressed by low-intensity exercise training. No significant alterations in sarco(endo)plasmic reticulum Ca2+ ATPase, phospholamban, or Na+/Ca2+ exchanger protein expression were found in response to training. Our results indicate that 6 mo of low-intensity exercise training delays the onset of decompensated HF and improves survival in the male SHHF rat. Similarly, exercise intervention prevented or suppressed alterations in several key variables that normally occur with the development of overt CHF. These data support the idea that exercise may be a useful and inexpensive intervention in the treatment of HF.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Blotting, Western; Calcium; Cell Separation; Cell Size; Citrate (si)-Synthase; Heart Failure; Isomerism; Leptin; Male; Myocardium; Myocytes, Cardiac; Myosin Heavy Chains; Physical Conditioning, Animal; Proteinuria; Rats; Rats, Inbred SHR; Survival Analysis

Dynamic exercise strongly affects atrial natriuretic peptides (ANP), in particular the mature bioactive alphaANP and the proANP fragments, namely proANP1-98, proANP1-30 and proANP31-67. The proANPs influence kidney functions and their plasma levels increase after physical exercise. We measured urinary proANP1-30 and proANP31-67 levels before and at the end of physical exercise in 28 well-trained male cyclists. For the first time, the proANP1-30 and proANP31-67 urinary levels in athletes before and at the end of a prolonged agonistic bicycle race were measured. Urinary creatinine and total proteins were also measured. The urinary proANP31-67, creatinine and total protein levels were significantly higher at the end of exercise than before. In contrast, proANP1-30/protein and proANP31-67/protein ratios decreased after exercise. Even proANP1-30/creatinine and proANP31-67/creatinine ratios were lower after exercise. A significant correlation between proANP1-30 and proANP31-67 urinary levels at the end of exercise was found. The proANP31-67/creatinine ratio before and after exercise also showed a significant correlation. The variation of urinary proANP fragments confirmed their possible role in physical exercise. In particular, it could be interpreted as a response of the body or kidney to renal impairment occurring during exercise.

Topics: Adolescent; Atrial Natriuretic Factor; Creatinine; Exercise; Humans; Kidney; Male; Peptide Fragments; Proteinuria; Urinalysis

In case-control studies, polymorphisms at the atrial natriuretic peptide gene (ANP) locus have been associated with presence of albuminuria in Type 1 and Type 2 diabetes. We evaluated the relationship between the ScaIand BstxI polymorphisms and albuminuria in the general population of the Mexico City Diabetes Study.. Allele/genotype frequencies were analysed by PCR-RFLP analysis using ScaI (wild, A(2) vs mutated, A(1)) and BstxI (wild, C(708) vs mutated, T(708)) enzyme.. Among 1288 subjects, hypertension was present in 112 subjects, Type 2 diabetes in 191 and impaired glucose tolerance in 136; microalbuminuria was present in 464 subjects, and clinical proteinuria in 199. General frequencies were 0.93 and 0.96 for the wild alleles, and 0.07 and 0.04 for the mutated alleles, respectively for ScaI and BstxI. Frequency of A(1)was 0.08 in normoalbuminuric, 0.05 in microalbuminuric, and 0.05 in proteinuric patients (chi(2)=7.3, p=0.025). Frequency of T(708) was 0.06 in normoalbuminuric and 0.03 microalbuminuric and 0.03 in proteinuric subjects (chi(2)=8.1, p=0.017). By multivariate analysis, the associations between A(1)or T(708) allele and albuminuria were independent of age, sex, BMI, diabetes, and hypertension, (odds ratio (OR) 0.60, p=0.01, (OR) 0.51, p=0.004, respectively).. In the general population of Mexico City, both polymorphisms of ANP are associated with albuminuria independently of hypertension, and could play a role in protecting subjects against development of albuminuria.

Topics: Adult; Albuminuria; Alleles; Atrial Natriuretic Factor; Deoxyribonucleases, Type II Site-Specific; Diabetes Complications; Diabetes Mellitus; Female; Gene Frequency; Glucose Intolerance; Humans; Hypertension; Male; Mexico; Middle Aged; Polymorphism, Genetic; Population; Proteinuria; Reverse Transcriptase Polymerase Chain Reaction

Nephrotic syndrome is characterized by severe proteinuria and sodium and water retention. Although endothelin (ET) 1 can cause natriuresis or antinatriuresis, the role played by ET-1 in proteinuria and in sodium retention due to nephrotic syndrome remains unclear.. We investigated the role played by the ET-1 system in sodium and water retention and in proteinuria in puromycin aminonucleoside induced nephrotic syndrome in rats using microdissected nephron segments, competitive polymerase chain reaction, and Western blot.. The expression of prepro ET-1, ET-converting enzyme 1 (ECE-1), and ET A receptor mRNAs, but not ET B receptor mRNA, in the glomeruli was increased in rats with nephrotic syndrome. The cGMP generation in the glomeruli induced by atrial natriuretic peptide and ET-1 was decreased, whereas the ET-3-induced cGMP generation was increased in rats with nephrotic syndrome. ECE-1 mRNA expression was increased not only in the glomeruli, but also in the thick ascending limbs and collecting ducts. The protein expression of ECE-1 was increased in the membrane fraction of the cortex and in the outer and the inner medulla of nephrotic rats. Blockade of ET A and B receptors by bosentan did not inhibit the occurrence of nephrotic syndrome. However, the administration of bosentan increased the urinary sodium excretion.. These data suggest that an activated ET-1-ET A receptor pathway in glomeruli and/or an increased ECE-1 mRNA expression in distal segments may participate in sodium and water retention, but not in the occurrence of nephrotic syndrome.

Topics: Animals; Aspartic Acid Endopeptidases; Atrial Natriuretic Factor; Bosentan; Cyclic GMP; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Endothelin-Converting Enzymes; Enzyme Induction; Gene Expression Regulation, Enzymologic; Kidney Glomerulus; Male; Metalloendopeptidases; Nephrons; Nephrotic Syndrome; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides; Time Factors

Previously we observed that atrial natriuretic peptide (ANP)-induced albuminuria was accompanied by an increase in urinary excretion of the low-molecular weight protein (LMW protein) beta2-microglobulin (beta2-m), suggesting that the albuminuria may at least partly be the result of blockade of tubular protein reabsorption. However, in our experiments ANP was dissolved in the polygeline Haemaccel (Hoechst, Behring-Werke, Marburg Germany) to prevent adhesion of ANP to the infusion system. Anecdotal reports have shown that high dosages of polygelines such as Haemaccel or Gelofusine (Braun NPBI Oss, the Netherlands) may influence tubular protein handling. In the present study we have evaluated the effect of a low and high doses of the polygeline Haemaccel on proteinuria. In addition, we have reassessed the effects of ANP.. We measured urinary beta2-microglobulin (beta2-m) and albumin excretion in healthy volunteers after infusion of a high-dose pure Haemaccel (0.04 mL kg(-1) min(-1) for 60 min), a low-dose Haemaccel (0.01 mL kg(-1) min(-1) for 60 min followed by infusion of 0.02 mL kg(-1) min(-1) for 60 min) and a low-dose Gelofusine (dose comparable to the low-dose Haemaccel). In addition we performed similar studies using ANP dissolved in saline and Haemaccel.. Infusion of Haemaccel caused a dose-dependent increase in urinary excretion of beta2-m. There were no differences between Haemaccel and Gelofusine. After infusion of ANP dissolved in Haemaccel urinary beta2-m excretion increased from 0.05 +/- 0.03 microg min(-1) to 27 +/- 10 microg min(-1) and urinary albumin excretion increased from 4.5 +/- 1.1 microg min(-1) to 9.7 +/- 6.3 microg min(-1) (P<0.05). During ANP + saline infusion, urinary beta2-m excretion did not change, whereas the urinary albumin excretion increased from 5.3 +/- 1.5 microg min(-1) to 7.9 +/- 2.4 microg min(-1) (P<0.05).. Our study demonstrates that even low doses of the polygelines Haemaccel and Gelofusine profoundly attenuate the tubular reabsorption of the low-molecular weight protein beta2-m. Atrial natriuretic peptide does not affect tubular protein reabsorption. Therefore, the rise in albuminuria during ANP infusion most likely reflects alterations in glomerular permeability.

Topics: Adult; Albuminuria; Anthropometry; Atrial Natriuretic Factor; beta 2-Microglobulin; Dose-Response Relationship, Drug; Female; Gelatin; Glomerular Filtration Rate; Humans; Male; Molecular Weight; Polygeline; Polymers; Proteinuria; Renal Circulation; Succinates

To prolong the half-life and enhance the biological activity of the human atrial natriuretic peptide (hANP), a peptide hormone, which is synthesized and released mainly by cardiac atrial myocytes and possesses potent natriuretic, diretic, and vasorelaxant properties.. The site-directed mutation technique based on polymerase chain reaction was performed to get the mutant of the human ANP gene (mhANP), and the retroviral expression vector, pLHY24, in which mhANP gene is under the transcriptional control of the human cytomegalovirus promoter, was constructed. The naked plasmid DNA of pLHY24 and positive control vector, pLHY19, in which the wild-type hNAP gene is in the same conditions as mhANP gene in pLHY24, and negative control vector, pLNCX without purpose gene, at a dose of 5 mg/kg body weight was injected intramuscularly into the rats with experimental renal disorder induced with adriamycin (ADR), respectively.. DNA sequencing result proved that the respected mhANP gene with the point mutations of TTC(131)/Phe-->TCC/Ser and ATG(135)/Met-->ATA/Ile has been obtained. In comparison with negative control group (87 +/- 7.1 pg/ml), a single intramuscular injection of expression vector harboring mhANP or hANP gene resulted in an obvious increase in plasma level of mhANP (107 +/- 7.8 pg/ml, t = 4.65, P < 0.01) or hANP (113 +/- 8.6 pg/ml, t = 5.71, P < 0.01) 5 days after injection. A significant elevation in the ratio of urine volume to body weight was occurred after both of mhANP gene and hANP gene delivery as compared with negative control and the effect lasted for more than 15 days. The diuretic activity of mhANP gene delivery was 1.6-, 2.0-, and 1.9-fold higher than that of hANP gene 5, 10, and 15 days after gene transfer, respectively. However, there were no statistical differences in the concentrations of K(+) and Na(+) in urine.. Both of mhANP and hANP gene delivery into the rats with experimental nephropathy could improve their directic function obviously and the diuretic activity of the former is stronger than that of the latter significantly.

Topics: Animals; Atrial Natriuretic Factor; Diuresis; Genetic Therapy; Kidney Diseases; Male; Mutagenesis, Site-Directed; Mutation; Proteinuria; Rats; Rats, Wistar

In order to explore the feasibility of gene therapy strategy based on the human atrial natriuretic peptide (hANP) gene delivery for the treatment of nephropathy and compare the diuretic activities of the hANP gene injected intramuscularly(i.m.) and intravenously(i.v.), the naked retroviral vector DNA harboring the hANP cDNA under the control of retroviral 5' long terminal repeat at a dose of 5 mg/kg body weight was injected i.m. or i.v. into the nephrotic model rats induced with adriamycin(ADR) injected i.v. at a dose of 7.5 mg/kg body weight. A single injection of the hANP gene resulted in a marked elevation in plasma level of hANP 5 days after gene delivery and a significant increase in the ratio of urine volume to body weight and the diuretic effect continued for more than 15 days. In addition, there was a significant rise in the body weight of treatment groups as compared with that of negative control group and no difference in the concentrations of electrolytes in urine between groups. There was no significant differences in total effects resulted from the two routes of gene delivery and the way of gene delivery through the skeletal muscle is simpler and easier. These results suggest that somatic gene delivery of the hANP gene could enhance the renal functions in nephrotic rats significantly and would be a potential strategy for the treatment of renal disorders.

Topics: Animals; Atrial Natriuretic Factor; Body Weight; Disease Models, Animal; Diuresis; Doxorubicin; Genetic Therapy; Humans; Injections, Intramuscular; Injections, Intravenous; Kidney Diseases; Proteinuria; Rats; Rats, Wistar

Albumin excretion is increased in persons with congestive heart failure (CHF), but the mechanism of this increase is unknown. Atrial natriuretic peptide (ANP) does not correlate with this albumin excretion, but the other 3 cardiac hormones derived from the ANP prohormone have never been investigated as to whether they can enhance albumin and/or protein excretion in persons with CHF.. Long-acting natriuretic peptide (LANP), vessel dilator, and kaliuretic peptide (100 ng/kg body weight/min) given intravenously for 60 minutes to NYHA Class III CHF patients (n = 24) increased the albumin excretion rate 2- to 7-fold (P <.001) and total protein excretion rate 2- to 5-fold (P <.001). These peptide hormones similarly enhanced beta(2)-microglobulin, a specific marker of proximal tubular reabsorption, excretion rate 25- to 40-fold (P <.0005) at the end of their respective infusions. Three hours after stopping their respective infusions, the beta(2)-microglobulin excretion rate was still 11- to 33-fold (P <.0005) increased.. LANP, vessel dilator, and kaliuretic peptide each enhance albumin and total protein excretion in persons with CHF. Part of the mechanism of this enhanced protein excretion is the inhibition of proximal tubular reabsorption of protein as shown by the beta(2)-microglobulin data.

Topics: Adult; Aged; Albuminuria; Atrial Natriuretic Factor; beta 2-Microglobulin; Heart Failure; Humans; Kidney Tubules, Proximal; Male; Middle Aged; Peptide Fragments; Protein Precursors; Proteinuria; Vasodilator Agents

Biologically active N-terminal fragments such as proANP(1-30), proANP(31-67), and proANP(1-98) derive from the prohormone of alpha-human atrial natriuretic peptide [proANP(99-126) or alpha-ANP]. No systematic data are available for patients with different kidney diseases.. Specific immunoassays were developed to determine plasma and urine concentrations of these fragments in 121 patients with different degrees of kidney function and urinary protein excretion, respectively.. In patients with kidney disease and normal renal function without proteinuria, circulating proANP(1-30) and proANP(31-67) increased 2.8-fold and 6.5-fold, respectively. Urinary excretion of proANP(31-67) increased by a factor of 7.7 in these patients, whereas proANP(1-30) was not affected. Patients with impaired renal function had a dramatic increase of urinary proANP(31-67) excretion even before serum creatinine levels started to rise. The progression of renal failure caused a significant rise of circulating proANP(1-30) (4.3-fold) and proANP(31-67) (3.0-fold) compared with patients with normal renal function. Urinary excretion of proANP peptides significantly increased, particularly when the serum creatinine level was> 5.0 mg/dL [proANP(1-30) 26-fold, proANP(31-67) 8.4-fold]. Urinary excretion of proANP(1-30) increased up to 4.4-fold and urinary excretion of proANP(31-67) increased up to 2.4-fold in patients with proteinuria in excess of 3 g/24 h.. Plasma concentrations and urinary excretion of proANP(1-30) and proANP(31-67) are affected by kidney disease and function, but not by proteinuria per se. It is proposed that the diseased kidney increases early urinary excretion of proANP fragments to participate in the regulation of renal function as well as sodium and water excretion.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Case-Control Studies; Creatinine; Female; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Peptide Fragments; Protein Precursors; Proteinuria

Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP).. SP were fed a high fat (24.5% in food) and high salt (1% in water) diet (SFD). Eprosartan (60 mg/kg/day) or vehicle (saline control) (n = 25/group) was administered by intraperitoneally-implanted minipumps to these SP on the SFD for 12 weeks. Normal diet fed SP and WKY rats (n = 25/group) were also included for comparison (i.e. served as normal controls). Mortality, hemodynamics, and both renal and cardiac function and histopathology were monitored in all treatment groups.. Eprosartan decreased the severely elevated arterial pressure (-12%; P < 0.05) produced by SFD but did not affect heart rate. Vehicle-treated SP-SFD control rats exhibited significant weight loss (-13%; P < 0.05) and marked mortality (50% by week 6 and 95% by week 9; P < 0.01). Eprosartan-treated SP-SFD rats maintained normal weight, and exhibited zero mortality at week 12 and beyond. Eprosartan prevented the increased urinary protein excretion (P < 0.05) that was observed in vehicle-treated SP-SFD rats. Echocardiographic (i.e. 2-D guided M-mode) evaluation indicated that SP-SFD vehicle control rats exhibited increased septal (+22.2%) and posterior left ventricular wall (+30.0%) thickness, and decreased left ventricular chamber diameter (-15.9%), chamber volume (-32.7%), stroke volume (-48.7%) and ejection fraction (-22.3%), and a remarkable decrease in cardiac output (-59.3%) compared to controls (all P < 0.05). These same parameters in eprosartan-treated SP-SFD rats were normal and differed markedly and consistently from vehicle-treated SP-SFD rats (i.e. treatment prevented pathology; all P < 0.05). Cardiac-gated MRI data confirmed the ability of eprosartan to prevent cardiac pathology/remodeling (P < 0.05). Histopathological analysis of hearts and kidneys indicated that eprosartan treatment significantly reduced end-organ damage (P < 0.01) and provided corroborative evidence that eprosartan reduced remodeling of these organs. Vehicle-treated SP-SFD rats exhibited a 40% increase in the plasma level of pro-atrial natiuretic factor that was reduced to normal by eprosartan (P < 0.05).. These data demonstrate that eprosartan, at a clinically relevant dose, provides significant end-organ protection in the severely hypertensive stroke-prone rat. It preserves cardiac and renal structural integrity, reduces cardiac hypertrophy and indices of heart failure, maintains normal function of the heart and kidneys, and eliminates premature mortality due to hypertension-induced end-organ failure.

Topics: Acrylates; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Heart Rate; Hypertension; Imidazoles; Kidney; Magnetic Resonance Imaging; Male; Myocardium; Natriuresis; Organ Size; Peptide Fragments; Protein Precursors; Proteinuria; Rats; Rats, Inbred SHR; Stroke; Survival Rate; Thiophenes; Ventricular Remodeling

Successful kidney transplantation normalizes elevated proatrial natriuretic peptide (proANP) plasma concentrations of renal failure patients in the early posttransplant period. We evaluated plasma and urinary proANP fragments in the late posttransplant period.. Immunoreactive proANP(1-30) and proANP(31-67) were determined in 389 renal transplant (Rtx) recipients in the long-term, follow-up period and in 16 healthy controls.. Rtx recipients had significantly higher concentrations of proANP(1-30) and proANP(31-67) in both plasma and urine than healthy controls. Although their graft function was normal, all of these long-term Rtx recipients were taking glucocorticoids, which increase proANP(1-30) and proANP(31-67) in the circulation to the extent found in this investigation. Two-thirds of these recipients were also taking cyclosporine, which also increases atrial peptides. Urinary proANP(31-67) was significantly higher than urinary proANP(1-30); 5.5-fold in Rtx patients and 2-fold in controls. Deterioration of renal graft function was associated with a rise of plasma proANP(1-30) from 0.98+/-0.66 to 6.28+/-3.55 nmol/l (P<0.0001) and plasma proANP(31-67) from 1.81+/-1.04 to 7.89+/-3.76 nmol/l (P<0.0001). Urinary excretion of proANP(1-30) increased from 0.27+/-0.34 to 5.96+/-5.07 nmol/24 hr (P<0.0001) and proANP(31-67) from 1.45+/-0.85 to 12.23+/-5.12 nmol/24 hr (P<0.0001). Also proteinuria enhanced plasma and urinary proANP fragments.. ProANP(1-30) and proANP(31-67) of Rtx recipients are affected by immunosuppression, hypertension, renal failure, and proteinuria. One would have expected proANP(1-30) and proANP(31-67) not to normalize because of the glucocorticoids that they were receiving.

Topics: Adult; Aged; Atrial Natriuretic Factor; Creatinine; Female; Humans; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Peptide Fragments; Postoperative Period; Protein Precursors; Proteinuria; Reference Values

To further elucidate the role of atrial natriuretic peptide (ANP) in preeclampsia, its metabolic clearance (MCRANP) was determined concomitantly with its effects on sodium excretion (UNa), glomerular filtration rate (GFR), and effective renal plasma flow (ERPF). Ten untreated preeclamptic primigravidae (PET) were studied at 29-37 wk gestation and again 4 mo postpartum (PP). Basal plasma concentration of ANP was significantly increased in PET compared with PP (14.8 +/- 1.9 vs. 4.1 +/- 0.5 pmol/l, respectively; P < 0.0001). MCRANP in PET and PP was 5.0 +/- 0.8 and 4.9 +/- 0.5 l/min [not significant (NS)], respectively. In PET, infusion of ANP produced (basal vs. ANP) a natriuresis (UNa 0.14 +/- 0.02 vs. 0.28 +/- 0.04 mmol/min, P < 0.001) and an increase in GFR (97 +/- 7 vs. 106 +/- 8 ml/min, P < 0.05), with ERPF unchanged (609 +/- 24 vs. 634 +/- 29 ml/min, NS). In PP, ANP infusion also produced a natriuresis (UNa 0.20 +/- 0.02 vs. 0.25 +/- 0.02 mmol/min, P = 0.01), no significant change in GFR (109 +/- 7 vs. 102 +/- 4 ml/min), and a significant reduction in ERPF (514 +/- 22 vs. 409 +/- 18 ml/min, P < 0.0001). Analysis of variance demonstrated a greater natriuretic effect of ANP in PET compared with PP (P < 0.05), similarly a significant difference in the effect of ANP on ERPF (P < 0.01) and GFR (P < 0.05) was seen but not on filtration fraction (P = 0.35).

Topics: Adult; Atrial Natriuretic Factor; Female; Gestational Age; Glomerular Filtration Rate; Hemodynamics; Humans; Infusions, Intravenous; Kidney; Metabolic Clearance Rate; Multivariate Analysis; Natriuresis; Parity; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Proteinuria; Regional Blood Flow; Renal Circulation; Sodium

The kidney damage in chronic glomerulonephritis develops not only as a result of causal immunopathological evens, but also due to chronic adaptation changes. The study was aimed at identification of active agents, which can serve as markers of proceeding adaptation changes and to determine, if these changes may be determined in patients undergoing the stage of remission of chronic glomerulonephritis.. The authors determined renin activity, concentration of atrium natriuretic peptide and endothelin in plasma and elimination of some prostanoids in urine in 33 patients with chronic stabilized glomerulonephritis with normal glomerular filtration and with normal blood pressure and in 21 healthy subjects. Seventeen patients without proteinuria did not receive therapy, 16 patients with minute proteinuria received 100 mg of acetylosalicylic acid daily. In the untreated patients without proteinuria, the elimination of thromboxane in urine was significantly higher than in both other groups. The plasma level of atrium natriuretic peptide in all 33 patients was significantly lower than in the healthy persons.. Based on this study the authors believe that adaptation changes proceed even in patients with chronic glomerulonephritis in clinical remission. The increased production of renal thromboxane, which can be successfully blocked by acetylosalicylic acid may be the marker of glomerular changes. A decreased level of atrium natriuretic peptide could reflect tubulointerstitial changes.

Topics: Adaptation, Physiological; Adult; Atrial Natriuretic Factor; Chronic Disease; Endothelins; Glomerular Filtration Rate; Glomerulonephritis; Humans; Middle Aged; Prostaglandins; Proteinuria; Renal Circulation; Renin; Vasomotor System

The cause of sodium retention in nephrotic syndrome is unclear. Hypovolaemia has traditionally been labelled as the cause but there is evidence in adults of a renal disturbance as the main cause. We aimed to find out whether children with early nephrosis can be classified as hypovolaemic by objective measures. We measured blood volume, kidney function, and hormone concentrations in children with early relapse of minimal-change nephrosis. Three presentations could be defined. The first was patients with incipient proteinuria and normal plasma protein, characterised by sodium retention, increased renal plasma flow, and slightly increased aldosterone, but normal noradrenaline. The second was patients with severe proteinuria, hypoproteinaemia, and hypovolaemic symptoms, who had oedema, sodium retention, and high concentrations of plasma renin, aldosterone, and noradrenaline, low atrial natriuretic peptide, and low glomerular filtration rate. The third was patients with equally severe proteinuria and hypoproteinaemia, but without hypovolaemic symptoms; they had oedema, but no active sodium retention, and normal plasma hormones and glomerular filtration. Neither blood pressure nor blood volume discriminated patients with or without hypovolaemic symptoms. These findings show that children with early full-blown nephrosis can present both with and without hypovolaemic symptoms and laboratory signs, despite equally severe hypoproteinaemia, and also that sodium retention precedes the reduction in serum protein.

Topics: Adolescent; Aldosterone; Atrial Natriuretic Factor; Blood Volume; Child; Child, Preschool; Female; Glomerular Filtration Rate; Humans; Hypoproteinemia; Kidney; Male; Nephrosis, Lipoid; Norepinephrine; Proteinuria; Renal Plasma Flow; Renin; Serum Albumin; Sodium

1. In order to determine whether atrial natriuretic peptide might play a role in the development of glomerular hyperfiltration in diabetes mellitus, we examined the effects of administration of glucose, albumin, atrial natriuretic peptide and an atrial natriuretic peptide receptor antagonist on renal function in rats with streptozotocin-induced diabetes mellitus and vehicle-treated control rats. 2. Four weeks after treatment, rats with diabetes mellitus had a higher mean plasma atrial natriuretic peptide concentration than controls [152 +/- 5 (SE) versus 115 +/- 6 pg/ml, P < 0.01] and a higher glomerular filtration rate (3.3 +/- 0.1 versus 2.7 +/- 0.2 ml min-1 kg-1, P < 0.05). 3. Infusion of albumin or glucose caused significant increases in atrial pressure, plasma atrial natriuretic peptide concentration and urinary excretion of sodium and protein in both groups of rats. 4. Increasing plasma atrial natriuretic peptide concentration by 60% via atrial natriuretic peptide infusion increased urinary excretion of sodium and protein in both control rats and rats with diabetic mellitus. 5. Administration of the atrial natriuretic peptide receptor antagonist HS-142-1 to diabetic rats resulted in diminished urinary excretion of both sodium (-61 +/- 14%, P < 0.02) and protein (-51 +/- 17%, P < 0.05). These changes were associated with a significant reduction in glomerular filtration rate (-32 +/- 11%, P < 0.05) and urinary cGMP excretion (-40 +/- 14%, P < 0.05). No significant effects of HS-42-1 on renal function were observed in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Diabetes Mellitus, Experimental; Glomerular Filtration Rate; Kidney Glomerulus; Male; Polysaccharides; Proteinuria; Rats; Rats, Wistar; Sodium; Time Factors

This study was designed to compare the renal effects of atrial (A-type) natriuretic peptide (ANP) on control (saline-injected) rats and rats with non-oliguric acute renal failure induced by cisplatin. The results obtained here are summarized as follows: (1) In the metabolic cage study, cisplatin-treated rats showed increases in blood urea nitrogen and serum creatinine while creatinine clearance decreased to the lowest levels on day 4. A transient increase in urinary protein was observed at day 4. (2) ANP infusion significantly increased urine flow rate (UFR), creatinine clearance (CCr), fractional excretion rates of sodium (FENa) and chloride (FECl), and urinary phosphorus and magnesium (Mg) excretions in a dose-dependent manner without affecting renal plasma flow and fractional excretion rates of potassium and urea in cisplatin-treated rats. (3) Renal effects of ANP on UFR, CCr, FENa, FECl and excretion of Mg were more pronounced in cisplatin-treated rats compared to control rats although markedly blunted responses to ANP have been reported in nephrotic patients and nephrotic animals induced by adriamycin and aminonucleoside. (4) Histological examination showed extensive necrosis of the S3 segment of the proximal tubule located in the outer stripe of the outer medulla with minimal glomerular abnormalities in the kidney of cisplatin-treated rats. In conclusion, the main mechanism of the increased renal responses to ANP is considered to be due to an increased delivery of sodium, fluid and ANP itself to the inner medullary collecting duct which is the major renal site of action of ANP under the condition of acute proximal tubular necrosis by cisplatin.

Topics: Acute Kidney Injury; Animals; Atrial Natriuretic Factor; Blood Pressure; Blood Urea Nitrogen; Cisplatin; Creatinine; Diuresis; Electrolytes; Infusions, Intravenous; Kidney; Kidney Medulla; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Reference Values; Renal Circulation; Time Factors

1. Disturbances of sodium and water homoeostasis may contribute to the close association between diabetes, hypertension and proteinuria. We therefore studied the patterns of two natriuretic hormones, plasma atrial natriuretic peptide and urinary dopamine, in 165 Chinese patients with non-insulin-dependent diabetes mellitus controlled by diet or oral hypoglycaemic agents on two occasions over a 6-week period. Patients were divided into three groups based on the mean value of two 24h urinary albumin excretion measurements. In group 1, 88 patients had normoalbuminuria (urinary albumin excretion < or = 30 mg/day), in group 2, 48 patients had microalbuminuria (urinary albumin excretion between 30 and 300 mg/day), and in group 3, 29 patients had macroalbuminuria (urinary albumin excretion > or = 300 mg/day). 2. The supine systolic blood pressure (mean +/- SD) was higher in patients with abnormal albuminuria (group 1: 140.9 +/- 27.4 mmHg; group 2: 158.1 +/- 26.4 mmHg; group 3: 166.7 +/- 23.9 mmHg; F = 13.1, P < 0.001, analysis of variance). Urinary sodium output was similar in these three groups of patients. The geometric means (anti-logarithm of 95% confidence interval logarithm) of plasma atrial natriuretic peptide concentrations increased with increasing proteinuria [group 1: 33.3 (29.9-37.1) pg/ml; group 2: 39.1 (34.2-44.6) pg/ml; group 3: 50 (38.6-54.7) pg/ml; F = 4.24, P < 0.01; analysis of variance], whereas those of urinary dopamine output were related inversely to proteinuria [group 1: 1291.7 (1167.2-1437.0) nmol/day; group 2: 1142.3 (975.9-1337.2) nmol/day; group 3: 982.7 (775.7-1245) nmol/day; F = 3.10, P < 0.05, analysis of variance].(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Atrial Natriuretic Factor; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dopamine; Humans; Hypertension; Middle Aged; Proteinuria

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Dipeptides; Drinking; Hypothalamus; Lisinopril; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Sodium; Urine

Atrial natriuretic peptide (ANP) increases proteinuria in primary glomerular disease. To study whether mesangial proliferation influences this effect, we infused alpha-human ANP at 25 ng/kg/min for 40 min into 6 patients with minor glomerular abnormalities (MGA), 10 with focal glomerulonephritis (FGN) and 8 with diffuse glomerulonephritis (DGN), and determined its renal effects. ANP significantly increased urinary excretions of Na and protein in all groups. Increases in urinary Na excretion were comparable among the groups (about + 200%), while increases in urinary protein excretion were greater in DGN than in the other two groups (DGN + 153 micrograms/min/1.73 m2, MGA + 77 micrograms/min/1.73 m2, FGN + 70 micrograms/min/1.73 m2). This increase was not related to the preinfusion level of proteinuria. Furthermore, the ratio of urinary protein to creatinine was significantly elevated by about 250% in the three groups. Thus, ANP seems to increase the permeability of the glomerular basement membrane to protein, particularly in patients with DGN, possibly through mesangial proliferation and the associated changes in adjacent tissues.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Blood Pressure; Female; Glomerulonephritis, Membranoproliferative; Humans; Infusions, Intravenous; Kidney; Male; Proteinuria

In order to evaluate the pathophysiologic role of a free form of atrial natriuretic peptide (ANP) in the nephrotic syndrome, the plasma concentration of immunoreactive ANP was measured by radioimmunoassay using direct (unextracted) and extraction methods in adriamycin-induced nephrotic and normal control rats. The ir-ANP levels measured using unextracted or extracted plasma were representative of total and the free form of ANP, respectively. The plasma levels of total and the free form of ANP were significantly higher in nephrotic rats than in controls (p less than 0.01, p less than 0.001). However, plasma levels of the bound form of ANP, calculated by subtracting the free form of ANP from total ANP, were comparable between the two groups. The free form of ANP was inversely correlated with the daily urinary sodium excretion (r = -0.71, p less than 0.001) and plasma albumin (r = -0.83, p less than 0.001), and positively correlated with the daily urinary protein excretion (r = -0.85, p less than 0.001) in both control and nephrotic groups. Based on these results, the preferential increase in the free form of ANP in nephrotic rats is considered to be a compensatory phenomenon induced by the decreased renal ability to eliminate sodium and water. An increase in the free form of ANP may have some role in urinary protein excretion in the nephrotic syndrome.

Topics: Animals; Atrial Natriuretic Factor; Doxorubicin; Male; Nephrotic Syndrome; Protein Binding; Proteinuria; Rats; Rats, Inbred Strains; Serum Albumin

Plasma values of atrial natriuretic factor (ANF) were evaluated in 31 women with pregnancy-induced hypertension (PIH) and 31 normal pregnant women at the same age of gestation. In 27 women with PIH and 27 normal pregnant women forearm venous tone (FVT) was evaluated by Strain Gauge Plethysmography. Forearm vascular resistance (FVR) was measured as the ratio of mean blood pressure (MBP) to forearm blood flow. In addition Cardiac Index (CI) by means of transthoracic electrical bioimpedance and total peripheral vascular resistance (TPR) (with the Frank Equation) were also measured. In comparison with the normal pregnant women, the women with PIH had similar values of hematocrit (as an index of plasma volume) and significantly higher levels of FVR and TPR, while ANF plasma values did not differ significantly. Subdividing the women with PIH in relation to the presence of proteinuria (greater than or equal to 0.3 g/l), those with proteinuria, in addition to significantly higher levels of FVR and TPR, had significantly higher levels of FVT than normal pregnant women, while ANF plasma values were higher even though the difference was only near the level of significance. Hypertensive women with proteinuria also had higher values of FVT than hypertensive women without proteinuria. By means of multiple regression ANF did not show any significant correlations with hematocrit or sodium excretion. Hypertension with proteinuria seems to represent a more severe form of the disease in which, in addition to the probable influence of other factors such as the renin-angiotensin and prostaglandin systems, a greater increase in peripheral sympathetic tone than in hypertension alone appears to be present, causing a reduction in venous compliance in addition to the elevation in FVR and TPR, with increase in central blood volume and atrial stretch. This may explain the higher ANF plasma levels in these patients in comparison with normal pregnant women, even though the absence of a significant correlation of ANF with hematocrit and the fact that ANF increase was only near the level of significance may suggest a change in the relation between ANF secretion and atrial volume receptors in pregnancy either normal or complicated by hypertension. ANF does not seem to play an important role in water and sodium excretion in PIH probably because of the presence of very high plasma levels of hormones such as aldosterone, progesterone and oestriol which, together with renal prostaglandins, s

Topics: Adult; Atrial Natriuretic Factor; Female; Hemodynamics; Humans; Hypertension; Natriuresis; Pregnancy; Pregnancy Complications, Cardiovascular; Proteinuria; Uric Acid; Vascular Resistance

Plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP) were measured with a specific radioimmunoassay in 19 undialysed patients with chronic renal failure. At the beginning, an extremely high level of plasma hANP (50 fmol/ml) seen in a patient was rejected with Smirnov's test and was excluded from further statistics. The plasma IR-ANP levels in these patients were significantly higher than those of 19 normal subjects matched with age and sex (10.9 +/- 1.6 vs 5.3 +/- 0.6 fmol/ml, mean +/- SEM, p less than 0.01), and positively correlated with mean blood pressure (r = 0.44, p less than 0.05) and the cardiothoracic ratio (r = 0.65, p less than 0.01), but did not correlate with creatinine clearance (r = -0.38, n.s.). Further, a significant correlation was observed between plasma IR-ANP and urinary protein output (r = 0.47, p less than 0.05). On the other hand, urinary protein output did not correlate significantly with variables such as mean blood pressure, the cardiothoracic ratio or creatinine clearance. Since it has been suggested that ANP enhances glomerular capillary permeability, increased ANP responding to volume overload in those patients may play an important role in increasing urinary protein excretion.

Topics: Adult; Age Factors; Aged; Aging; Atrial Natriuretic Factor; Blood Pressure; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Radioimmunoassay; Sex Factors

The effects of atrial natriuretic peptide (ANP) on urinary protein excretion were examined in patients with renal parenchymal diseases (RPD, n = 18) and those with diabetes mellitus (DM, n = 12). Before and 30 min after intravenous injection of ANP (50 micrograms), urine samples were collected. ANP injection increased urinary volume and urinary sodium excretion in both groups. In RPD, urinary protein excretion (UprV) increased by 87% (1.5 +/- 0.7 [SEM] to 2.8 +/- 1.1 mg/min, p less than 0.05). ANP also increased UprV in patients with diabetic nephropathy [N(+); 1.7 +/- 0.8 to 5.0 +/- 2.5 mg/min, p less than 0.05] and those without nephropathy [N(-); 0.10 +/- 0.02 to 0.22 +/- 0.07 mg/min, p less than 0.05]. Since ANP increased creatinin clearance in both groups (+9.4 +/- 2.5 ml/min in RPD and +24.1 +/- 3.5 ml/min in DM, p less than 0.01 for both), urinary protein to creatinine excretion ratios (UprV/UcrV) were determined, which should be a parameter of glomerular protein permeability. The UprV/UcrV ratio increased by 48% (p less than 0.01) and 24% (p less than 0.05) in RPD and in DM, respectively. ANP did not change urinary composition of albumin and globulin. In RPD, increases in UprV by ANP were positively related to the basal serum creatinin levels (r = 0.57, p less than 0.01). In DM group, ANP-induced increases in the UprV/UcrV ratio were higher in the N(+) subgroup than in the N(-) subgroup (+0.8 +/- 0.4 vs +0.09 +/- 0.04, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Diabetes Mellitus; Female; Humans; Kidney Diseases; Male; Middle Aged; Proteinuria

Low dose iv infusion (0.01 and 0.03 micrograms/kg per min, for 30 min each) of alpha-human atrial natriuretic factor (alpha-hANF) produced a significant increase (+300%) in urinary protein excretion in patients with essential hypertension but not in normotensive controls, when their renal function was normal. The major component of excreted proteins induced by alpha-hANF infusion was presumed to be albumin on the basis of molecular weight (69,000) analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. Urine output and sodium and potassium excretion rates were increased dose-dependently by alpha-hANF infusion in the hypertensive patients in a similar fashion to those in the controls. Glomerular filtration rate (GFR) remained unchanged in the controls but was slightly increased in the patients (+33%) during the infusion. These results suggest that besides its previously recognized physiological functions such as natriuresis and diuresis, ANF plays an important role in the regulation of renal handling of proteins in patients with essential hypertension.

Topics: Adult; Atrial Natriuretic Factor; Electrophoresis, Polyacrylamide Gel; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Molecular Weight; Natriuresis; Potassium; Proteinuria

The effects of a single intravenous injection of 100 mg/kg puromycin aminonucleoside (PAN) on renal protein, electrolyte, and fluid excretion as well as inulin and lithium clearances in rats were investigated under basal conditions, after iso-oncotic blood volume expansion with bovine serum albumin (BSA) and during infusion of atrial natriuretic peptide (ANP). All treated rats developed severe proteinuria 7-28 days after injection. On day 17, the protein excretion of the PAN group was 1,050 +/- (SE) 118 micrograms/(min x kg body weight) compared with 42.3 +/- 3.9 micrograms/(min x kg body weight) in the control group. Hypoproteinemia, edema or ascites were not observed. The renal protein excretion increased dramatically after BSA infusion and even more during ANP infusion in the PAN group. The PAN-treated animals lost about 62% of the infused BSA during the time of the experiment. No significant changes in protein excretion were observed in the controls. Both groups had similar basal excretions of urine volume, sodium, chloride, and potassium and responded to the BSA and PAN infusions with comparable increases in these parameters. The glomerular filtration rate was slightly, but not significantly higher in the PAN group during the control periods. Increases after BSA and ANP occurred in both groups, reaching significance only in the control group. Proximal tubular function was slightly impaired in PAN-treated rats as judged from a lower increase of the fractional excretion of lithium after BSA. Mean arterial blood pressure was higher in the PAN group (136.2 +/- 2.4 vs. 127.0 +/- 2.2 mm Hg) and fell in both groups to a comparable degree after BSA infusion. A further fall in blood pressure occurred after ANP infusion. Plasma ANP immunoreactivity was not different between the groups and increased after BSA infusion. Our data demonstrate that severe glomerular lesion as indicated by proteinuria can be observed after PAN administration without impairment of distal tubular function as judged from sodium and fluid excretion, and therefore support the view that the sodium retention observed in nephrotic syndrome is due to a separate intrarenal defect rather than a consequence of protein loss.

Topics: Animals; Atrial Natriuretic Factor; Male; Proteinuria; Puromycin; Puromycin Aminonucleoside; Rats; Rats, Inbred Strains; Serum Albumin, Bovine; Sodium

1. The effects of synthetic alpha-human atrial natriuretic peptide (alpha-hANP) on urinary protein excretion were examined in nine healthy subjects and 20 patients with primary glomerular diseases who had proteinuria of 1.0 g or more per day. Synthetic alpha-hANP was intravenously infused into supine subjects at a rate of 8.3 pmol min-1 kg-1 for 40 min. 2. Before alpha-hANP infusion, the plasma concentration of immunoreactive alpha-hANP was significantly higher in the patients with glomerulonephritis than in the normal subjects (44.3 +/- 8.7 vs 19.4 +/- 3.0 pmol/l, mean +/- SEM, P less than 0.01) and it showed a positive correlation with mean arterial pressure (rs = 0.84, P less than 0.001) and a negative correlation with creatinine clearance (rs = -0.50, P less than 0.01). 3. During infusion of alpha-hANP, although the urinary excretion of protein did not change significantly in the normal subjects, it increased from 0.6 +/- 0.2 to 3.0 +/- 0.8 mg min-1 m-2 (P less than 0.001) in the patients with glomerulonephritis. The urinary protein/creatinine ratio did not change significantly in the former (from 0.18 +/- 0.05 to 0.22 +/- 0.06; NS), whereas it rose from 3.25 +/- 0.94 to 7.62 +/- 1.31 (P less than 0.001) in the latter. 4. The urinary excretions of albumin and of alpha 1-, alpha 2-, beta- and gamma-globulins, which were electrophoretically analysed, all increased in eight nephrotic patients during or immediately after infusion of alpha-hANP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Albuminuria; Atrial Natriuretic Factor; Creatinine; Female; Glomerular Filtration Rate; Glomerulonephritis; Hematocrit; Humans; Kidney; Male; Middle Aged; p-Aminohippuric Acid; Proteinuria; Renin; Sodium; Time Factors

Adriamycin (ADR) nephrosis and a model of unilateral ADR-induced proteinuria were produced in Sprague-Dawley (S.D.) rats to investigate the mechanism of sodium retention by the nephrotic kidney. Plasma volume, as measured by the dilution principle using radioiodinated serum albumin, was significantly higher in nephrotic animals than in control ones (NS: 69.61 +/- 15.02: control: 47.05 +/- 5.32 ml/kg: P less than 0.01). Similarly plasma levels of immunoreactive ANP (iANP) were significantly higher in nephrotic animals compared to controls (NS 104.22 +/- 36.41: control 59.94 +/- 20.88 pg/ml; P less than 0.05). Using the unilateral model we found a markedly reduced diuretic and natriuretic response to the infusion of synthetic rat atrial natriuretic peptide (ANP 1-28) in proteinuric kidney but not in contralateral kidney, despite a comparable increase in glomerular filtration rate. To explain the blunted diuresis and natriuresis in the presence of normal glomerular response to ANP, we investigated the possibility of an abnormality at post-glomerular level by studying ANP receptor density and affinity of the inner stripe of outer medulla and the inner medulla in ADR-and vehicle-treated rats. The inner stripe of outer medulla and the inner medulla receptor density and affinity were not significantly different in ADR rats as compared to animals given the vehicle alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Proteins; Disease Models, Animal; Doxorubicin; Glomerular Filtration Rate; Kidney Cortex; Male; Nephrotic Syndrome; Plasma Volume; Proteinuria; Radioimmunoassay; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Sodium

Atrial natriuretic peptide (ANP) and arginine vasopressin concentrations were measured in 9 patients with pregnancy-induced hypertension. The results were compared to those found in 7 normal pregnant women matched for age, duration of pregnancy, and parity. Plasma ANP levels were significantly higher in the pregnancy-induced hypertension patients than in the control group. Plasma arginine vasopressin concentrations, however, were not significantly different in the two populations. The mechanism of the observed rise in ANP concentrations in the patients with pregnancy-induced hypertension is not known. However, it may be related to a rise in intra-atrial pressures secondary to hypertension, an increase in baroreceptor discharge as a result of hypertension, or, less likely, the ANP may be released from extracardiac sites.

Topics: Adult; Arginine Vasopressin; Atrial Natriuretic Factor; Creatinine; Female; Humans; Pre-Eclampsia; Pregnancy; Proteinuria; Uric Acid

In this study we investigated circulating atrial natriuretic factor (ANF) concentrations in patients with different stages of diabetic nephropathy. Type 1 diabetic patients with incipient or overt nephropathy had elevated plasma ANF concentrations when compared with nonnephropathic diabetics and normals. Patients having a hyperfiltration only, which might be a risk factor for the development of diabetic nephropathy, had also elevated ANF concentrations. No correlation could be found between ANF concentrations and blood pressure, diabetes duration, age, or parameters of metabolic control. These findings may indicate a role of ANF in the development of diabetic nephropathy. Long-term follow-up studies should be performed to assess the prognostic and diagnostic importance of plasma ANF determinations in diabetic patients.

Topics: Adult; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Male; Proteinuria; Reference Values

Atrial natriuretic peptide (ANP) and the renin-angiotensin-aldosterone system are important regulatory hormones in sodium homeostasis. We have measured these hormones during volume expansion produced by water immersion in diabetic subjects without and with microalbuminuria or frank proteinuria and compared the response with normal controls. Diabetic subjects excreted about half the amount of sodium that was excreted by the normal subjects (39 vs 21 mmol) over 4 h. Diabetic subjects and normal ones showed a twofold rise in ANP during immersion and a marked suppression of both plasma renin activity and aldosterone. There was no difference in the hormonal response between diabetic and normal subjects or between those diabetic subjects with and those without incipient (microalbuminurics) or established nephropathy.

Topics: Adult; Aldosterone; Atrial Natriuretic Factor; Blood Volume; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Immersion; Male; Middle Aged; Natriuresis; Proteinuria; Renin; Renin-Angiotensin System