Renal Water Metabolism Research Articles

Er Shen Wan extract alleviates polyuria and regulates AQP 2 and AVPR 2 in a rat model of spleen-kidney Yang deficiency–induced diarrhea

Ethnopharmacological relevanceEr Shen Wan (ESW), has been empirically used for treating spleen-kidney Yang deficiency (SKYD) syndrome in Traditional Chinese medicine (TCM) for centuries and shows a variety of activities. The medicinal formula is a mixture of two component herbs, Psoraleae Fructus (PF, Bu-Gu-Zhi in Chinese) and Myristicae Semen (MS, Rou-Dou-Kou in Chinese). The current study was designed to evaluate ESWP antidiuretic treatment of polyuria and to explore potential mechanisms of renal water metabolism in the rat model of SKYD-induced diarrhea. Materials and methodsAn animal model of ‘SKYD–induced diarrhea syndrome’ has been established to evaluate the therapeutic effect and action mechanism according to the clinical syndrome and symptoms. The optimal dose (3.5 g/kg) of ESWP was given to rats by gavage for two weeks. Urinary volumes after 24 h were recorded. After the end of the trial, macroscopic morphological and histological examination of the kidney were conducted. Serum levels of Arginine vasopressin (AVP) and aldosterone (ALD) were also measured. Additionally, quantitative real-time RT-PCR (RT-qPCR) and immunohistochemistry (IHC) analyses were performed to clarify the regulation of aquaporin 2 (AQP 2) and arginine vasopressin type 2 receptor (AVPR 2) in the kidney at the gene and tissue expression levels respectively. ResultsAfter the administration of ESWP, urinary output volume after 24 h was found to be significantly decreased in rats. Elevated plasma levels of AVP and ALD were detected. Histological kidney damage appeared to be impeded, and histological disease scores were reduced. In addition, the expression levels of AQP 2 and AVPR 2 were significantly increased. ConclusionThis study suggests that ESWP may elicit significant effects on the treatment of polyuria. Potential mechanisms at least partially involve hormone regulation, and alleviating renal pathological damage. Simultaneously, ESWP may alter renal water absorption by increasing AQP 2 and AVPR 2 expression levels. Thus, the in vivo experimental evidence indicates that ESWP has a therapeutic effect on the SKYD syndrome, which is consistent with its traditional usage.

Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolality

In vitro studies suggest that endothelin-1 (ET-1) inhibits vasopressin (AVP)-stimulated water permeability in the collecting duct (CD). To evaluate the role of CD-derived ET-1 in regulating renal water metabolism, the ET-1 gene was selectively disrupted in the CD (CD ET-1 KO). During normal water intake, urinary osmolality (Uosm), plasma Na concentration, urine volume, and renal aquaporin-2 (AQP2) levels were unchanged, but plasma AVP concentration was reduced in CD ET-1 KO animals. CD ET-1 KO mice had impaired ability to excrete an acute, but not a chronic, water load, and this was associated with increased CD ET-1 mRNA in control, but not CD ET-1 KO, mice. In response to continuous infusion of 1-desamino-8-D-arginine vasopressin, CD ET-1 KO mice had greater increases in Uosm, V2 and AQP2 mRNA, and phosphorylation of AQP2. CD suspensions from CD ET-1 KO mice had enhanced AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ET-1 KO increases renal sensitivity to the urinary concentrating effects of AVP and suggest that ET-1 functions as a physiological autocrine regulator of AVP action in the CD.

Effect of the V 1a/V 2-AVP receptor antagonist, Conivaptan, on renal water metabolism and systemic hemodynamics in rats with cirrhosis and ascites

Background: Selective V 2-AVP receptor antagonists are effective in inducing aquaresis in humans and rats with cirrhosis, hyponatremia and water retention. However, it is unknown whether dual V 1a/V 2-AVP antagonists are also efficacious as aquaretic agents under these conditions. This is important, particularly considering that blockade of V 1a-AVP receptors could aggravate cardiocirculatory function in decompensated cirrhosis. Aims: To evaluate the renal, hormonal and hemodynamic effects induced by the chronic oral administration of the V 1a/V 2-AVP antagonist, Conivaptan, in rats with CCl 4-induced cirrhosis, ascites and severe water retention. Methods: We assessed the aquaretic efficacy of 10-day chronic oral administration of Conivaptan (0.5 mg/kg body weight (bw)) in cirrhotic rats with hyponatremia and water retention. Urine volume (UV), osmolality (UOsm), and sodium excretion (U NaV) were measured daily. At the end of the study arterial pressure was also measured. Results: Conivaptan produced an acute increase in UV, a reduction in UOsm and, at the end of the investigation, cirrhotic rats receiving the V 1a/V 2-AVP receptor antagonist did not show hyponatremia or hypoosmolality. Conivaptan also normalized U NaV without affecting creatinine clearance and arterial pressure. Conclusions: Dual V 1a/V 2-receptor antagonists may be therapeutically useful for the treatment of water retention and dilutional hyponatremia in human cirrhosis.

Cyclooxygenase-1 derived prostaglandins are involved in the maintenance of renal function in rats with cirrhosis and ascites.

1. The maintenance of renal function in decompensated cirrhosis is highly dependent on prostaglandins (PGs). Since PG synthesis is mediated by cyclooxygenase-1 and -2 (COX-1 and COX-2), the present study was designed to examine which COX isoform is involved in this phenomenon. 2. Renal COX-1 and COX-2 protein expression and distribution were analysed by Western blot and immunohistochemistry in nine rats with carbon tetrachloride-induced cirrhosis and ascites and 10 control animals. The effects of placebo and selective COX-1 (SC-560) and COX-2 (celecoxib) inhibitors on urine flow (V), urinary excretion of sodium (U(Na)V) and PGE(2) (U(PGE2)V), glomerular filtration rate (GFR), renal plasma flow (RPF), the diuretic and natriuretic responses to furosemide and renal water metabolism were assessed in 88 rats with cirrhosis and ascites. 3. COX-1 protein levels were found to be unchanged in kidneys from cirrhotic rats. In contrast, these animals showed enhanced renal COX-2 protein expression which was focally increased in the corticomedullary region. Although U(PGE2)V was equally reduced by SC-560 and celecoxib, only SC-560 produced a significant decrease in U(Na)V, GFR and RPF and a pronounced impairment in the diuretic and natriuretic responses to furosemide in rats with cirrhosis and ascites. Neither SC-560 nor celecoxib affected renal water metabolism in cirrhotic rats. 4. These results indicate that despite abundant renal COX-2 protein expression, the maintenance of renal function in cirrhotic rats is mainly dependent on COX-1-derived prostaglandins.

Physiology and pathophysiology of renal aquaporins.

The discovery of aquaporin-1 (AQP1) by Agre and associates answered the longstanding biophysical question of how water specifically crosses biological membranes. In the kidney at least 7 aquaporins are expressed at distinct sites. AQP1 is extremely abundant in the proximal tubule and descending thin limb and is essential for urinary concentration. AQP2 is exclusively expressed in the principal cells of the connecting tubule and collecting duct and is the predominant vasopressin-regulated water channel. AQP3 and AQP4 are both present in the basolateral plasma membrane of collecting duct principal cells and represent exit pathways for water reabsorbed apically via AQP2. Studies in patients and transgenic mice have shown that both AQP2 and AQP3 are essential for urinary concentration. Three additional aquaporins are present in the kidney. AQP6 is present in intracellular vesicles in collecting duct intercalated cells and AQP8 are present intracellularly at low abundance in proximal tubules and collecting duct principal cells but the physiological function of these 2 channels remain undefined. AQP7 is abundant in the brush border of proximal tubule cells and is likely to be involved in proximal tubule water reabsorption. A series of studies have underscored crucial roles of aquaporins for regulation of renal water metabolism and hence body water balance. Moreover it has become clear that dysregulation of aquaporins, and especially AQP2 is critically involved in many water balance disorders. Lack of functional AQP2 is seen in primary forms of diabetes insipidus, and reduced expression and targeting is seen in several diseases associated with urinary concentrating defects such as acquired nephrogenic diabetes insipidus, postobstructive polyuria, as well as acute and chronic renal failure. In contrast, in conditions with water retention such as severe congestive heart failure, pregnancy and SIADH both AQP2 expression levels and apical plasma membrane targetting is increased suggesting a role for AQP2 in the development of water retention. Continued analysis of the aquaporins is providing detailed molecular insight into the fundamental physiology and pathophysiology of water balance and water balance disorders.

Key Roles of Renal Aquaporins in Water Balance and Water-Balance Disorders

The discovery of aquaporins by Agre and co-workers provided an answer to the long-standing biophysical question of how water can pass cell membranes. The identification and characterization of several aquaporins expressed in the kidney has allowed detailed insight, at the molecular level, into the fundamental physiology and pathophysiology of renal water metabolism.

Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites

Background & Aims: The critical role of cyclooxygenase (COX) products in maintenance of renal function in cirrhosis with ascites discourages the use of nonsteroidal anti-inflammatory drugs in this disease. The recent development of selective COX-2 inhibitors opens new avenues for the use of these compounds in decompensated cirrhosis. The current study evaluates the effects of a selective COX-2 inhibitor (SC-236) on renal function in cirrhotic rats with ascites. Methods: In protocol 1, urine volume, urinary excretion of sodium and prostaglandins, glomerular filtration rate, and renal plasma flow were measured before and after administration of SC-236 (n = 12) or ketorolac (n = 10) to rats with cirrhosis. Protocol 2 was aimed at assessing the effects of COX inhibitors on renal water metabolism in 28 cirrhotic rats. Results: Administration of SC-236 to cirrhotic animals did not produce significant renal effects, whereas administration of the nonselective COX-1/COX-2 inhibitor, ketorolac, resulted in a marked reduction in urine volume, urinary excretion of prostaglandins, and glomerular filtration rate and in a significant impairment in renal water metabolism. Conclusions: These findings indicate that SC-236 does not significantly impair renal function in rats with cirrhosis. GASTROENTEROLOGY 1999;116:1167-1175

Aquaretic effect of the κ-opioid agonist RU 51599 in cirrhotic rats with ascites and water retention

Background & Aims: It has recently been described that κ-opioid receptor agonists inhibit antidiuretic hormone secretion and promote water excretion in humans and experimental animals. The aim of this study was to evaluate the aquaretic efficacy of the κ-opioid receptor agonist RU 51599 in conscious cirrhotic rats with ascites and water retention. Methods: In protocol 1, arterial pressure, heart rate, and renal water metabolism were measured in basal conditions and then were measured for 120 minutes after the administration of Ringer's solution (n = 8; 0.4 mL) or RU 51599 (n = 7; 1 mg/kg). In protocol 2, plasma antidiuretic hormone concentration was measured (n = 6) before and 60 minutes after administration of RU 51599 (1 mg/kg). In protocol 3, the effect of RU 51599 (n = 9; 1 mg/kg) was compared with that of the V 2-receptor antagonist SKF 100398 (n = 9; 30 μg/kg). Results: RU 51599 administration induced a profound diuretic and aquaretic effect without altering arterial pressure and heart rate. In protocol 2, the κ-opioid agonist reduced by about 50% plasma antidiuretic hormone levels (from 6.6 ± 0.9 to 3.4 ± 0.6 pg/mL; P < 0.05). Finally, the improvement in renal water metabolism induced by RU 51599 was similar to that produced by the V 2-receptor antagonist. Conclusions: RU 51599 has a potent aquaretic effect in cirrhotic rats with water retention, suggesting that κ-opioid receptor agonists may be useful for the treatment of water retention and dilutional hyponatremia in cirrhosis.

Blockade of the hydroosmotic effect of vasopressin normalizes water excretion in cirrhotic rats

Water retention in cirrhosis has classically been considered to be due to a low distal fluid delivery secondary to increased proximal sodium reabsorption. However, recent studies showing high plasma vasopressin levels in patients and rats with cirrhosis, ascites, and dilutional hyponatremia suggest that a nonosmotic vasopressin hypersecretion could be an alternative mechanism. To investigate the role of vasopressin in water retention in cirrhosis, the renal ability to excrete a water load (50 ml/kg body wt), as estimated by the minimum urinary osmolality and the percentage of the water load excreted during 3 h, was assessed in 10 control rats and in 20 cirrhotic rats with ascites and impaired water excretion and high urinary excretion of vasopressin. Twenty-four hours later, the same procedure was repeated in cirrhotic rats 20 min after the subcutaneous injection (30 μg/kg body wt) of d(CH2)5Tyr(Et) VAVP, an antagonist of the hydroosmotic effects of vasopressin (10 rats), or the vehicle (10 rats). Treatment with the vasopressin antagonist normalized water excretion in 9 of the 10 rats. No significant changes in renal water metabolism were observed in the group of rats given the vehicle. These results indicate that vasopressin hypersecretion is the predominant mechanism of the impairment in water excretion in rats with experimental cirrhosis and ascites.

The blockade of the hydro-osmotic effect of antidiuretic hormone (ADH) normalizes renal water metabolism in experimental cirrhosis with ascites

The blockade of the hydro-osmotic effect of antidiuretic hormone (ADH) normalizes renal water metabolism in experimental cirrhosis with ascites

Disordered Water Metabolisms: Hyponatremia

Normal osmoregulation is maintained by the proper function and interplay of factors influencing thirst, renal water metabolism, and vasopressin secretion. In pathophysiologic states, body water homeostasis is disrupted and hyponatremia ensures. Hyponatremia associated with cardiac failure, hepatic failure, respiratory failure, diabetes mellitus, the postoperative state, and other disorders is commonly found in the critical care setting. The pathophysiology, diagnosis, and treatment of hyponatremia are discussed.

Evidence that renal prostaglandins are involved in renal water metabolism in cirrhosis

Plasma antidiuretic hormone (ADH) and urinary prostaglandin E2 excretion (UPGE2V) were measured in basal conditions, after water restriction, and after water-loading in 10 normal subjects (free water clearance after the water load, CH2O, 9.6 +/- 0.8 ml/min) and in 27 patients with cirrhosis and ascites (13 with a positive CH2O: 3.6 +/- 0.5; 14 with a negative CH2O: -0.37 +/- 0.007). Plasma ADH and UPGE2V were significantly increased in patients with a positive CH2O as compared with normal subjects. Patients with a negative CH2O showed a significantly higher plasma ADH and a lower UPGE2V and GFR than did normal subjects and patients with the positive CH2O. In 18 additional subjects (6 normal and 12 with cirrhosis, ascites, and a positive CH2O) submitted to a sustained water overload, the i.v. administration of 450 mg of lysine acetylsalicylate (LAS) induced a marked reduction of UPGE2V, but it had no effect on plasma ADH. LAS did not alter GFR and CH2O in normal subjects; however, it reduced CH2O in all the 12 patients (from 5.1 +/- 0.4 to 0.6 +/- 0.3) and the GFR in only 6 of these patients. These results suggest (a) that renal PGE2 plays an important role in the maintenance of water excretion in cirrhosis with ascites, and (b) that impaired ability to dilute the urine in cirrhosis may be a consequence of the simultaneous occurrence of impaired renal hemodynamics, nonostomic hypersecretion of ADH, and reduced renal production of PGE2.

The effect of osmotic stimuli on prolactin secretion and renal water excretion in normal man and in chronic hyperprolactinemia.

An osmoregulatory role for prolactin (PRL) in man has been postulated, and PRL secretion has been reported to be influenced by osmotic stimuli. Clinical observation, however, does not support this notion. The effects of water loading, hypertonic saline infusion and nicotine on serum PRL and on renal water metabolism were investigated in 6 normal subjects and in 8 patients with chronic hyperprolactinemia (four with and four without demonstrable pituitary tumors). None of the patients had thyroid, adrenal or vasopressin deficiency. Renal walter handling in these patients was indistinguishable from normal. Likewise, serum PRL was not affected by the stimuli employed in either the normal subjects or the patients. No correlation between degree or duration of hyperprolactinemia and renal water metabolism was found. It is concluded that PRL is not an important osmoregulatory hormone in man.

Specific stimulation and inhibition of renal prostaglandin release by angiotensin analogs.

Specific stimulation and inhibition of renal prostaglandin release by angiotensin analogs.

Release of prostaglandin-like material from dog kidney during nerve stimulation

Canine kidneys were autoperfused in situ at constant flow in 28 experiments. Renal venous effluent was examined for (PLM) prostaglandin-like material following acidic lipid extraction and thin layer chromatography or by continuous bioassay utilizing the bloodbathed organ technique. There was a low basal efflux of PLM from the kidney which was markedly enhanced during the renal vascular constriction elicited by renal nerve stimulation at 2-10 cycles/second or by infusion of norepinephrine. The PLM was tentatively identified as an E-type prostaglandin based on chromatographic behavior and bioassay. The present study indicates that PLM is released from the dog kidney during an increase in renal vascular resistance. Release is not necessarily dependent upon changes in total renal blood flow although alterations in the distribution of intrarenal blood flow might be involved. (authors)