Microalbuminuria in Rats Treated with D-Nitroarginine Methyl Ether.

Microalbuminuria is an early symptom and prognostic marker of the progression of renal pathology. The analysis of the role of anionic components of the renal glomeruli in the albumin retention and the development of a model of minimal changes in the glomerular filter leading to the appearance of microalbuminuria are relevant. The effect of organic cations D-arginine methyl esters (D-AME) and D-nitroarginine (D-NAME) on the excretion of albumin by the kidneys in rats was studied. D-AME had no effect on urinary albumin excretion in rats. D-NAME caused microalbuminuria, which persisted for more than a day and sharply increased after injection of vasopressin. The number of anionic sites labeled with polyethyleneimine decreased in the structures of the glomerular filter. D-NAME-induced microalbuminuria can later serve as a model for studying nephroprotective or damaging factors.

Role of Proglucagon Peptides in Osmoregulation.

Glucagon-like peptide-1 (GLP-1), a product of partial proteolysis of proglucagon, is involved not only in regulation of carbohydrates, but also in water-salt metabolism. The study examined the role of proglucagon derivatives GLP-1, GLP-2, and oxyntomodulin in rat osmoregulation. Of them, only blood plasma GLP-1 increased in response to water load (20 ml/kg). Administration of glucose (1.5 g/kg) elevated GLP-1 and oxyntomodulin but did not change the level of GLP-2. GLP-1 accelerated excretion of excess water during hyperhydration, whereas GLP-2 decreased this parameter. No physiological effects of oxyntomodulin in the kidneys were revealed. Probably, the blood levels of proglucagon derivatives are independently regulated for each peptide. In contrast to GLP-2 and oxyntomodulin, GLP-1 is involved in osmoregulation.

Subtypes of Neurohypophyseal Nonapeptide Receptors and Their Functions in Rat Kidneys.

The nonapeptides of neurohypophysis, vasotocin and mesotocin, detected in most vertebrates, are replaced by vasopressin and oxytocin in mammals. Using bioinformatics methods, we determined the spectrum of receptor subtypes for these hormones in mammals and their physiological effects in the kidneys of rats. A search for sequences similar to the vertebrate vasotocin receptor by proteomes and transcriptomas of nine mammalian species and the rat genome revealed three subtypes of vasopressin receptors (V1a, V1b, and V2) and one type of oxytocin receptors. In the kidneys of non-anesthetized rats, which received a water load of 2 ml per 100 g of body weight, three effects of vasopressin were revealed: 1) increased reabsorption of water and sodium, 2) increased excretion of potassium ions, and 3) increased excretion of sodium ions. It has been suggested that each of the effects on the kidney is associated with selective stimulation of the vasopressin receptor subtypes V2, V1b, and V1a depending on the concentration of nonapeptide. In experiments on non-anaesthetized rats with a water load, the injection of oxytocin reduces the reabsorption of solute-free water in the kidneys and increases the excretion of sodium ions. The possible physiological mechanisms behind the realization of both effects with the participation of a single type of oxytocin receptors are being analyzed. Thus, the spectrum of activated receptor subtypes varies depending on the current concentration of neurohypophyseal hormones, as a result of which the predominant effect on renal function changes, which ensures precise regulation of water-salt homeostasis.

The mechanism of glucagon-like peptide-1 participation in the osmotic homeostasis.

We have found the physiological mechanism of intensification of the excessive fluid removal from the body under the action of glucagon-like peptide-1 and its analog exenatide. Under the water load in rats, exenatide significantly increased the clearance of lithium, reduced fluid reabsorption in the proximal tubule of the nephron and intensified reabsorption of sodium ions in the distal parts, which contributed to the formation of sodium-free water and faster recovery of osmotic homeostasis. Blocking this pathway with a selective antagonist of glucagon-like peptide-1 receptors slowed down the elimination of excessive water from the body.

Effects of Selective Agonists of V1a, V2, and V1b Receptors on Sodium Transport in Rat Kidney.

The role of subtypes of vasopressin receptors in modulation of renal sodium reabsorption was studied in in vivo experiments on Wistar rats. Selective V1a receptor agonist reduced sodium reabsorption in the kidneys and expression of these receptors increased by practically 100 times. This effect was similar to the effect of furosemide. Selective V2 receptor agonist enhanced sodium reabsorption in the kidney and simultaneously increased reabsorption of solute-free water. Stimulation of V1b receptors did not affect sodium transport. Our findings attest to the key role of V1a receptors in the regulation of renal excretion of sodium ions.

[EFFECTS OF ORALLY AND PARENTERALLY ADMINISTERED ANALOGS OF PEPTIDE HORMONES ON RENAL WATER AND ION TRANSPORT].

In experiments with female Wistar rats it was shown that analogs of neurohypophysial hormones administered to gastrointestinal tract preserved their specific physiological activity - they increased solute-free water reabsorption and urinary sodium and potassium excretion. Doses of deamino-vasotocin exerted antidiuretic and natriuretic effects following its oral administration were 50 and 200 times higher compared to maximal effective ones after intramuscular injection. Inhibition of gastrointestinal proteases by aprotinine enhanced effects of nonapeptides; the amount of peptide absorbed from the intestine under these conditions was approximately 0.5 % of orally introduced substance. In contrast to analogs of neurohypophysial nonapeptides, glucagon-like peptide-1 mimetic (exenatide) did not exert its physiological effects after oral administration, whereas it increased urinary sodium and potassium excretion following intramuscular injection.

[PHYSIOLOGICAL APPROACH TO RESTORING OSMOTIC HOMEOSTASIS IN RATS WITH HYPERNATREMIA].

The aim of the study was a search of physiological approach to restoring osmotic homeostasis in rats with hypernatremia. Intraperitoneal administration of 1.8 ml/100 g BW 2.5% NaCl solution to Wistar rats induced hyperosmia (306 +/- 1 mOsm/kg H2O) and hypernatremia (150.3 +/- 0.3 mM in 60 min of experiment), increase in urinary sodium excretion (from 8 +/- 1 to 230 +/- 10 micromol/100 g BW for 2 h). Under these conditions enhancement of natriuresis up to 465 +/- 29 micromol/100 g BW and 667 +/- 24 micromol/100 g BW for 2 h was observed after injections of vasopressin analogue, deamino-vasotocin (dAVT, 0.05 microg/100 g BW), or loop diuretic, furosemide (1 mg/100 g BW), respectively. dAVT-induced natriuresis was accompanied by increase in solute-free water reabsorption; serum osmolality (301 +/- 1 mOsm/kg H2O) and sodium concentration (145.8 +/- 0.5 mM) were close to normal values by 60 min of experiment. Furosemide caused relatively greater excretion of water, than sodium; hypernatremia (150.2 +/- 0.4 mM) and hyperosmia (311 +/- 1 mOsm/kg H2O) persisted during 60 min of experiment. Thus, in rats with hypernatremia dAVT due to decrease in renal sodium reabsorption and increase in solute-free water reabsorption promotes recovery of serum osmolality and sodium concentration.

[Effects of neurohypophysial nonapeptides and their analogues on magnesium excretion by rat kidney].

Effects of neurohypophysial nonapeptides of vertebrates (vasopressin, vasotocin, and their synthetized analogues) on urinary magnesium excretion were studied in rats. Neurohypophysial hormones and their analogues at doses stimulating V2-receptors (0.0001-0.001 nmol/100 g BW) produced antidiuretic effect and reduced urinary magnesium excretion. At the higher doses activating V2- and V1a-receptors (0.025-0.1 nmol/100g BW), vasotocin and its analogues (deamino-vasotocin (dAVT), deamino-Thr4-vasotocin, deamino-hArg8-vasotocin, deaminomonocarbo-vasotocin) enhanced excretion of magnesium and sodium ions. Direct relation between increase in renal excretion of sodium and magnesium ions was found under these conditions. dAVT induced 10 times lesser increase in magnesium excretion after administration of a V1a-receptor antagonist. An antagonist of V2-receptors did not affect the dAVT-induced magniuresis. The obtained data suggest that V-receptors take part in regulation of magnesium transport in rat kidney.

[Comparison of reabsorption of osmotically free water in the bud and energy of interaction of vasotocin analogs with a V2-receptor].

The calculated values of the binding energy of nonapeptides with receptors in docking with their influence on reabsorption of osmotically free water in a rat bud in vivo were compared. Vasotocin and some its analogs were intramuscularly introduced to non-narcotized rat females of the Wistar line in doses from 0.1 pmol to 0.5 nmol/kg of body weight against the background of peroral water load (50 ml/kg of body weight). A significant correlation between the calculated interaction energy of peptides with V2-receptors and an increase of reabsorption of osmotically free water in the rat bud stimulated by injection of nonapeptides was found. The results evidence that alterations in rat bud in vivo caused by analogs of vasotocin and their interactions with V2-receptors can be accurately simulated.