cyclic-gmp and Nephrotic-Syndrome

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Edema; Humans; Kidney; Nephrotic Syndrome; Rats; Sodium

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

The edema formation in nephrotic syndrome (NS) is associated with a blunted response to atrial natriuretic peptide (ANP). The natriuretic effects of ANP have been related to renal dopamine D1-receptors (D1R). We examined the interaction between ANP and renal D1R in rats with puromycin aminonucleoside-induced NS (PAN-NS). Urinary sodium, cyclic guanosine monophosphate (cGMP) excretion, and D1R protein expression and localization in renal tubules were evaluated in PAN-NS and control rats before and during volume expansion (VE). The effects of zaprinast (phosphodiesterase type 5 inhibitor), alone or in combination with Sch-23390 (D1R antagonist), were examined in both groups. The increased natriuresis and urinary cGMP excretion evoked by acute VE were blunted in PAN-NS despite increased levels of circulating ANP. This was accompanied in PAN-NS by a marked decrease of D1R expression in the renal tubules. Infusion of zaprinast in PAN-NS resulted in increased urinary excretion of cGMP and sodium to similar levels of control rats and increased expression of D1R in the plasma membrane of renal tubular cells. Combined administration of Sch-23390 and zaprinast prevented natriuresis and increased cGMP excretion induced by zaprinast alone. We conclude that D1R may play a major role in the ANP resistance observed in PAN-NS.

Topics: Animals; Atrial Natriuretic Factor; Benzazepines; Cyclic GMP; Glomerular Filtration Rate; Homeostasis; Kidney; Male; Natriuresis; Nephrotic Syndrome; Purinones; Puromycin Aminonucleoside; Rats; Receptors, Dopamine D1; Sodium

The serine/threonine protease corin, which proteolytically activates atrial natriuretic peptide (ANP), is reduced in the kidneys of animals with nephrotic syndrome and glomerular nephritis. Polzin et al. provide evidence for a linkage between the decreased corin and β-epithelial sodium channel, phosphodiesterase 5, and cGMP-dependent protein kinase II in the nephrotic kidney. They propose that decreases in cGMP resulting from the reduced corin may be responsible for the Na(+) retention and volume expansion that are hallmarks of these kidney diseases.

Topics: Absorption; Animals; Atrial Natriuretic Factor; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Nephrotic Syndrome; Serine Endopeptidases; Sodium

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

Nephrotic syndrome is associated with resistance to the renal actions of atrial natriuretic peptide (ANP). We performed experiments in anesthetized, acutely nephrectomized rats 21-28 days after injection of adriamycin (7-8 mg/kg i.v.) or 9-14 days after injection of anti-Fx1A antiserum (5 ml/kg i.p.) (passive Heymann nephritis; PHN) to test whether extrarenal resistance also occurred. Proteinuria was significantly elevated in both models compared with controls before study. ANP infusion (1 microgram.kg-1.min-1) caused arterial pressure to decrease similarly in control rats, adriamycin-treated rats, and rats with PHN (by 8.2 +/- 1.0, 9.4 +/- 2.3, and 9.0 +/- 2.0%, respectively; all P < 0.05 vs. both baseline and vehicle-infused control rats). In control rats, hematocrit increased progressively to a maximal value 9.5 +/- 0.9% over baseline as a result of the infusion, an increase corresponding to a reduction in plasma volume of 16.1 +/- 0.9%. The ANP-induced increase in hematocrit was preserved in adriamycin-treated rats (9.2 +/- 1.3%) but was markedly blunted in rats with PHN (2.4 +/- 1.3%; P < 0.0001 vs. ANP infusion in control rats). ANP infusion increased plasma ANP levels to the same extent in the three groups, whereas plasma guanosine 3',5'-cyclic monophosphate was significantly lower in rats with PHN compared with both control and adriamycin-treated rats. Infusion of a subpressor dose of angiotensin II (ANG II, 2.5 ng.kg-1.min-1) fully restored the ANP-induced increase in hematocrit in rats with PHN. This study demonstrates that 1) the hemoconcentrating and hypotensive actions of ANP are preserved in adriamycin-treated rats, 2) the effect of ANP on hematocrit and fluid distribution is blunted in rats with PHN while its hypotensive action is preserved, and 3) low-level ANG II infusion normalizes the hemoconcentrating effect of exogenously infused ANP in rats with PHN. Thus deficient ANG II generation in rats with PHN, but not adriamycin nephrosis, may contribute to extrarenal ANP resistance.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Proteins; Blood Volume; Cyclic GMP; Doxorubicin; Glomerulonephritis; Hematocrit; Hemodynamics; Male; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley

To evaluate therapeutic and side effects, atrial natriuretic peptide (ANP) was administered as a pharmacological bolus dose (2 micrograms/kg body weight) to 7 patients with nephrotic syndrome and to 13 age- and gender-matched control subjects. The basal glomerular filtration rate was similar, but the blood pressure was slightly higher in the patients than in the controls. Injection of ANP induced a significant increase of sodium excretion in controls (from 0.21 to 0.52 mmol/min, medians, p < 0.01), but not in nephrotics (from 0.21 to 0.32 mmol/min). Urinary output and free water clearance after ANP had been given were also lower in the patients. The natriuretic effect was mediated through inhibition of distal tubular fractional sodium reabsorption, as estimated by the lithium clearance technique, and through an increase of glomerular filtration rate, both effects only significant in the healthy subjects. The blood pressure was reduced to the same extent in the two groups. Although similar levels of ANP were reached in the groups after injection, cyclic guanosine monophosphate (GMP)/ANP was less in the patients, both basally and after ANP injection, and the urinary excretion of cyclic GMP did not increase in the nephrotics (from 478 to 1,220 pmol/min, ns) as in the controls (from 389 to 2,500 pmol/min, p < 0.01). The urinary albumin excretion rate increased significantly in patients, whereas the prostaglandin E2 excretion increased after ANP administration only in controls. Endothelin, angiotensin II, aldosterone, and arginine vasopressin were unchanged in the two groups. Basal aldosterone was lower and ANP higher in patients than in controls. In conclusion, the natriuretic effect of ANP was reduced in nephrotic patients. This could not be attributed to counterregulatory haemodynamic or hormonal factors, but probably to reduced second messenger cyclic GMP.

Topics: Adult; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Body Water; Case-Control Studies; Cyclic GMP; Dinoprostone; Endothelins; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Injections, Intravenous; Male; Middle Aged; Nephrotic Syndrome; Renal Plasma Flow; Sodium

We examined renal sodium handling in rats with Hymann nephritis (HEN), an immunologically mediated model of nephrotic syndrome. Rats were studied 9-14 days following i.p. injection of anti-Fx1A antiserum. We previously demonstrated that HEN had a blunted volume expansion natriuresis (2% body weight isotonic saline infused over 5 min), excreting sodium at only half the rate of normal controls (CTL) despite similar increase in plasma atrial natriuretic peptide (ANP) concentration. Urinary excretion of cGMP accumulation by isolate glomeruli and inner medullary collecting duct (IMCD) cells in response to increasing concentration of ANP, and RNP (also called urodilatin). Results (fmol/mg prot/10 min) are means +/- SEM: [table: see text]. Basal accumulation of cGMP was not different among the groups, HEN rats hd reduced cGMP accumulation in response to ANP, and RNP. In binding studies using 125I-ANP, no difference in either density or affinity was found between CTL and HEN rats. Thus, there is a renal resistance to ANP in rats with HEN, which can be extended to other agents acting through the cGMP pathway. This resistance is not due to impaired binding of ANP, but to impaired accumulation of cGMP in responsive tissues, reflecting perhaps increased cGMP catabolism by phosphodiesterase. Such an observation may account for the altered sodium handling in nephrotic rats.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Diuretics; Drug Resistance; Immune Sera; Male; Natriuresis; Nephrotic Syndrome; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor

Adriamycin-induced nephrotic syndrome in the rat is associated with a blunted natriuretic response to infusion of atrial natriuretic factor. To study the mechanism of renal hyporesponsiveness to the peptide in rats with experimental nephrosis, we evaluated the effects of the hormone on renal production of cGMP, the second messenger of the hormone. Baseline GFR and sodium excretion were lower in nephrotic as compared with normal controls. Infusion of synthetic rat atrial natriuretic factor (10 micrograms/kg/h) increased fractional sodium excretion by 7.3 +/- 2.4% in control rats but only by 1.4 +/- 0.5% in adriamycin-treated rats (P less than 0.05). However, the increments in urinary nucleotide excretion rate (UcGMP x V/GFR), in response to atrial natriuretic factor infusion, were comparable in control and nephrotic rats (control, 114.7 +/- 16.1 pmol/mL; adriamycin, 95.5 +/- 12.0 pmol/mL; P was not significant). The in vitro generation of cGMP in response to incremental doses of the hormone (10(-11) to 10(-6) M + 1 mM 3-isobutyl methyl xanthine) was of similar magnitude in isolated glomeruli derived from control (2.4 +/- 0.25 to 9.1 +/- 1.0 pmol/mg of protein) and nephrotic rats (2.9 +/- 0.2 to 10.3 +/- 1.0 pmol/mg of protein) and was not impaired in suspensions of medullary tissue derived from nephrotic rats (control, 8.4 +/- 0.6 to 14.2 +/- 1.2 pmol/mg of protein; adriamycin, 7.3 +/- 0.7 to 22.0 +/- 2.4 pmol/mg of protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Doxorubicin; In Vitro Techniques; Kidney Glomerulus; Kidney Medulla; Male; Natriuresis; Nephrotic Syndrome; Rats; Rats, Inbred Strains

Experimental nephrotic syndrome results in sodium retention, reflecting, at least in part, an intrinsic defect in renal sodium handling in the distal nephron. We studied the relationships among plasma atrial natriuretic peptide (ANP) concentration, sodium excretion (UNaV), and urinary cyclic GMP excretion (UcGMPV) in vivo, and the responsiveness of isolated glomeruli and inner medullary collecting duct (IMCD) cells to ANP in vitro, in rats with adriamycin nephrosis (6-7 mg/kg body weight, intravenously). 3-5 wk after injection, rats were proteinuric and had a blunted natriuretic response to intravenous infusion of isotonic saline, 2% body weight given over 5 min. 30 min after onset of the infusion, plasma ANP concentrations were elevated in normals and were even higher in nephrotics. Despite this, nephrotic animals had a reduced rate of UcGMPV after the saline infusion, and accumulation of cGMP by isolated glomeruli and IMCD cells from nephrotic rats after incubation with ANP was significantly reduced compared to normals. This difference was not related to differences in binding of 125I-ANP to IMCD cells, but was abolished when cGMP accumulation was measured in the presence of 10(-3) M isobutylmethylxanthine or zaprinast (M&B 22,948), two different inhibitors of cyclic nucleotide phosphodiesterases (PDEs). Infusion of zaprinast (10 micrograms/min) into one renal artery of nephrotic rats normalized both the natriuretic response to volume expansion and the increase in UcGMPV from the infused, but not the contralateral, kidney. These results show that, in adriamycin nephrosis, blunted volume expansion natriuresis is associated with renal resistance to ANP, demonstrated both in vivo and in target tissues in vitro. The resistance does not appear related to a defect in binding of the peptide, but is blocked by PDE inhibitors, suggesting that enhanced cGMP-PDE activity may account for resistance to the natriuretic actions of ANP observed in vivo. This defect may represent the intrinsic sodium transport abnormality linked to sodium retention in nephrotic syndrome.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Cyclic GMP; Glomerular Filtration Rate; Kidney Glomerulus; Kidney Tubules, Collecting; Male; Natriuresis; Nephrotic Syndrome; Rats; Rats, Sprague-Dawley

Blood volume, plasma concentrations of atrial natriuretic peptide, guanosine cyclic monophosphate (cGMP), angiotensin II, aldosterone and arginine vasopressin, and urinary excretion rate of prostaglandin E2, cGMP, sodium, and water were determined before and after intravenous administration of frusemide 0.75 mg/kg body-weight in nine patients with the nephrotic syndrome and 15 control subjects. The decrease in blood volume and the increase in urinary sodium and water excretion after fusemide were significantly reduced in the nephrotic patients compared with the controls. Atrial natriuretic peptide was reduced after frusemide both in patients (6.2 to 4.9 pmol/l, medians, P less than 0.05) and controls (5.9 to 4.8 pmol/l, P less than 0.01), but the nadir was delayed in the patients, and cGMP in plasma and urine was reduced only in the controls. The angiotensin II increase was delayed in the patients and aldosterone increased only in the controls. Basal urinary excretion of prostaglandin E2 was less in the nephrotic patients than in the controls (P less than 0.05), but after frusemide the prostaglandin E2 excretion rate increased in the patients (0.25 to 0.62 pmol/min, P less than 0.05), but not in the controls (0.46 to 0.39 pmol/min). In conclusion, reduced water and sodium excretion after frusemide in the nephrotic syndrome is accompanied by a diminished reduction of blood volume, a delayed decrease in atrial natriuretic peptide, and a blunted increase in angiotensin II and aldosterone compared with healthy subjects. Sodium excretion after frusemide may be more dependent on PGE2 production in nephrotic patients than in healthy subjects.

Topics: Adult; Aldosterone; Angiotensin II; Arginine Vasopressin; Atrial Natriuretic Factor; Blood Volume; Body Water; Cyclic GMP; Dinoprostone; Female; Furosemide; Humans; Male; Middle Aged; Nephrotic Syndrome; Sodium

The physiological mechanism regulating secretion of alpha-human atrial natriuretic polypeptide (alpha hANP) was studied by measuring plasma alpha hANP (P alpha hANP) with radioimmunoassay during water immersion (WI). Twelve healthy volunteers and sixteen patients with nephrotic syndrome were immersed in water for 4 hours. During WI, alpha hANP level and urinary cGMP excretion (UcGV) increased significantly both in volunteers and patients, the urinary volume (UV) and urinary Na excretion (UNaV) also increased significantly. The mean peak values of alpha hANP and UcGV in volunteers were significantly lower than those in the patients, whereas the mean values of UV and UNaV in the former were significantly higher than those in the latter. The increase in alpha hANP level in volunteers correlated positively with the increase of UNaV, UV and UcGV during WI. The close correlations between the increased alpha hANP level and the increased UNaV, UV and UcGV was shown in the patients. These results suggest that alpha hANP is released into the circulation by acute central hypervolemia and plays a physiologically important role in maintaining water and electrolytes homeostasis in normal subjects and that the increased alpha hANP level in nephrotic syndrome makes compensatory regulation in water and electrolytes disorders.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Female; Humans; Immersion; Male; Middle Aged; Natriuresis; Nephrotic Syndrome; Sodium

We followed the renal and hormonal effects of physiological intravenous infusions of atrial natriuretic factor (ANF) in 6 water-loaded patients with nephrotic syndrome and 7 healthy subjects. Two of the patients had impaired renal function, 3 had active sodium retention, and none took drugs. The ensuing natriuresis, increase in plasma and urinary cyclic guanosine monophosphate and suppression of the renin-aldosterone axis were similar in normals and nephrotics. In both groups, significant increases in filtration fraction (inulin/PAH clearance) were observed, and in the nephrotics, major increases also occurred in both the absolute and fractional urinary albumin excretion. The renal and hormonal responses to ANF are not impaired in the nephrotic syndrome.

Topics: Adult; Albuminuria; Atrial Natriuretic Factor; Cyclic GMP; Female; Humans; Infusions, Intravenous; Kidney; Male; Nephrotic Syndrome; Renin-Angiotensin System