cyclic-gmp and Polyuria

Aristolochic acid (AA) nephropathy (AAN), a progressive tubulointerstitial injury of toxic origin, is characterized by early and transient acute tubular necrosis. This process has been demonstrated to be associated with reduced nitric oxide (NO) production, which can disrupt the regulation of renal function. In this study, we tested the hypothesis that L-arginine (L-Arg) supplementation could restore renal function and reduce renal injury after AA intoxication. C57BL/6 J male mice were randomly subjected to daily i.p. injection of either sterile saline solution or AA (2.5 mg kg(-1)) for 4 days. To determine whether AA-induced renal injuries were linked to reduced NO production, L-Arg, a substrate for NO synthase, was supplemented (5%) in drinking water. Mice intoxicated with AA exhibited features of rapid-onset acute kidney injury, including polyuria, significantly increased plasma creatinine concentrations, proteinuria and fractional excretion of sodium (P < 0.05), along with severe proximal tubular cell injury and increased NADPH oxidase 2 (Nox2)-derived oxidative stress (P < 0.05). This was associated with a significant reduction in NO bioavailability. L-Arg supplementation in AA-treated mice significantly increased NO bioavailability, which in turn improved renal function (creatininaemia, polyuria, proteinuria, fractional excreted sodium and N-acetyl-β-D-glucosaminidase enzymuria) and renal structure (tubular necrosis and tubular cell apoptosis). These changes were associated with significant reductions in Nox2 expression and in production of reactive oxygen species and with an increase in antioxidant concentrations. Our results demonstrate that preservation of NO bioavailability leads to renal protection in AA-induced acute kidney injury by reducing oxidative stress and maintaining renal function.

Topics: Acute Kidney Injury; Animals; Arginine; Aristolochic Acids; Creatinine; Cyclic GMP; Kidney; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Oxidative Stress; Polyuria; Proteinuria; Sodium; Superoxide Dismutase

Lithium (Li)-treated patients often develop urinary concentrating defect and polyuria, a condition known as nephrogenic diabetes insipidus (NDI). In a rat model of Li-induced NDI, we studied the effect that sildenafil (Sil), a phosphodiesterase 5 (PDE5) inhibitor, has on renal expression of aquaporin-2 (AQP2), urea transporter UT-A1, Na(+)/H(+) exchanger 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (NKCC2), epithelial Na channel (ENaC; α-, β-, and γ-subunits), endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase. We also evaluated cGMP levels in medullary collecting duct cells in suspension. For 4 wk, Wistar rats received Li (40 mmol/kg food) or no treatment (control), some receiving, in weeks 2-4, Sil (200 mg/kg food) or Li and Sil (Li+Sil). In Li+Sil rats, urine output and free water clearance were markedly lower, whereas urinary osmolality was higher, than in Li rats. The cGMP levels in the suspensions of medullary collecting duct cells were markedly higher in the Li+Sil and Sil groups than in the control and Li groups. Semiquantitative immunoblotting revealed the following: in Li+Sil rats, AQP2 expression was partially normalized, whereas that of UT-A1, γ-ENaC, and eNOS was completely normalized; and expression of NKCC2 and NHE3 was significantly higher in Li rats than in controls. Inulin clearance was normal in all groups. Mean arterial pressure and plasma arginine vasopressin did not differ among the groups. Sil completely reversed the Li-induced increase in renal vascular resistance. We conclude that, in experimental Li-induced NDI, Sil reduces polyuria, increases urinary osmolality, and decreases free water clearance via upregulation of renal AQP2 and UT-A1.

Topics: Animals; Aquaporin 2; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Diabetes Insipidus, Nephrogenic; Drinking; Epithelial Sodium Channels; Glomerular Filtration Rate; Kidney; Kidney Medulla; Lithium Compounds; Male; Membrane Transport Proteins; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Piperazines; Polyuria; Purines; Rats; Sildenafil Citrate; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sodium-Potassium-Chloride Symporters; Solute Carrier Family 12, Member 1; Sulfones; Urea Transporters

To investigate the effects of Yiniao Recipe, a compound traditional Chinese herbal medicine, on contents of serum antidiuretic hormone, and plasma cyclic adenosine monophosphate and cyclic guanosine monophosphate in rats with kidney-yang deficiency.. Forty male Wistar rats were randomly divided into blank control group, untreated group, desmopressin (Minirin) group, low-dose Yiniao Recipe group and high-dose Yiniao Recipe group, with 8 rats in each group. Rats in the blank control group were injected with 0.2 mL normal saline, and rats in the other groups were given intramuscular injection of hydrocortisone 25 mg/kg, 1 time daily for 21 consecutive days; from the 8th day of injection, rats were given double distilled water, Minirin, and high- and low-dose Yiniao Recipe respectively for 30 days. Before and after treatment, 24-hour urine volume was observed, and serum antidiuretic hormone (AVP) as well as plasma cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) contents were detected by enzyme-linked immunosorbent assay. The cAMP/cGMP ratio and morphological changes in renal tissues were also observed.. Compared with blank control group, 24-hour urine volume, serum AVP content and cAMP/cGMP ratio in the untreated group were decreased; compared with the untreated group, Minirin and Yiniao Recipe at low and high doses reduced 24-hour urine volume and increased serum AVP content and cAMP/cGMP ratio significantly (P<0.05 or P<0.01). There were no obvious pathological changes in renal tissue in all groups.. Yiniao Recipe may reduce 24-hour urine volume by increasing serum AVP content and regulating the ratio of cAMP to cGMP in kidney-yang deficiency rats.

Topics: Animals; Cyclic AMP; Cyclic GMP; Drugs, Chinese Herbal; Male; Phytotherapy; Polyuria; Rats; Rats, Wistar; Vasopressins; Yang Deficiency

Patients with paroxysmal supraventricular tachycardia (SVT) may have a polyuria after termination of tachycardia. There is increasing evidence that the renal peptide urodilatin (ANP (95-126))--and not plasma ANP (ANP (99-126))--is the member of the natriuretic peptide family mediating natriuresis and diuresis in man. In patients with SVT we, therefore, analyzed the relationship between diuresis, natriuresis, plasma ANP, urinary urodilatin excretion and renal excretion of cyclic GMP, the second messenger in the ANP system. During and after clinical presentation with spontaneously occurring SVT, two patients with AV-nodal and one patient with atrioventricular reentry tachycardia (heart rate 160 to 200 bpm) were studied. Urinary urodilatin excretion was correlated to diuresis (r = 0.73) and natriuresis (r = 0.93); similarly urinary cyclic GMP excretion was related to diuresis (r = 0.80) and natriuresis (r = 0.87; p < 0.001, respectively). In contrast, there was no significant correlation between plasma ANP concentrations and diuresis (r = 0.28, n.s.) or natriuresis (r = 0.11, n.s.). As an explorative analysis, stepwise multiple linear regression identified urinary urodilatin as the most important contributor to diuresis and natriuresis after SVT. These data on polyuria after spontaneous SVT further support the view that in man urodilatin is the member of the natriuretic peptide family participating in kidney physiology.

Topics: Adult; Atrial Natriuretic Factor; Cyclic GMP; Diuresis; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Natriuresis; Peptide Fragments; Polyuria; Regression Analysis; Tachycardia, Paroxysmal; Tachycardia, Supraventricular

Studies have indicated the involvement of a glutamatergic mechanism in lithium (Li+) action. Glutamatergic agonists, such as kainic acid, are known to promote the synthesis of nitric oxide (NO) and to increase cGMP, while Li+ has displayed a similar, yet unexplained, ability to increase cGMP. NO synthesis is regarded as the principal prodromal event leading to the activation of the guanyl cyclase-cGMP transduction mechanism. In the present study, the involvement of the NO:cGMP pathway in the action of Li+ was examined, while the possibility of a glutamatergic mechanism in this response was also investigated. Parameters examined included cortical accumulation of cGMP and the stable oxidative metabolites of NO, viz. NO2- and NO3-, collectively expressed as NO2-. A significant positive correlation was observed in the in vivo cGMP and NO2- data throughout all the groups. Chronic treatment of rats with LiCl (0.3% m/m) engendered a significant increase in cGMP levels which was inhibited by the NO-synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME). Acute administration of kainic acid resulted in an increased accumulation of NO2-, also prevented by concomitant L-NAME administration. In addition, a synergistic stimulatory response on cortical NO2- was observed in the combination of LiCl and kainic acid. Collectively, these data implicate an involvement of a glutamatergic-mediated NO:cGMP transduction mechanism in the action of Li+.

Topics: Animals; Arginine; Cerebral Cortex; Cyclic GMP; Drinking Behavior; Glutamates; Kainic Acid; Lithium Chloride; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Polyuria; Rats; Rats, Wistar; Stereotyped Behavior