Adenosine A2 a receptor stimulation prevents proteinuria in diabetic rats by promoting an anti-inflammatory phenotype without affecting oxidative stress.

AIM: Diabetic patients are at increased risk for kidney disease. There is presently no clinical treatment available that effectively protects kidney function in diabetics. This study investigates whether chronic stimulation of the adenosine A2a receptor (A2a AR) protects kidney function in insulinopenic diabetic rats. METHODS: Streptozotocin-induced diabetic rats and corresponding controls were chronically treated with the adenosine A2a AR agonist CGS21680 throughout the four-week diabetes duration. Kidney function was thereafter investigated, and urine and plasma samples were collected for analysis of protein, oxidative stress and inflammatory markers. RESULTS: Glomerular filtration rate, renal blood flow, filtration fraction and diabetes-induced kidney hypoxia were all unaffected by chronic A2a AR stimulation. Furthermore, diabetic rats had increased oxidative stress, which was further increased by chronic A2a AR stimulation. However, the 10-fold increased urinary protein excretion observed in the diabetic rats was completely prevented by chronic A2a AR stimulation. These beneficial effects were accompanied by reduced levels of the pro-inflammatory TNF-α and increased levels of the anti-inflammatory IL-10 as well as decreased infiltration of macrophages, glomerular damage and basement membrane thickness. CONCLUSION: Chronic A2a AR stimulation prevents proteinuria and glomerular damage in experimental diabetes via an anti-inflammatory mechanism independent of oxidative stress and kidney hypoxia.

Changing dopaminergic activity through different pathways: consequences for renal sodium excretion, regional blood flow and oxygen tension in the rat.

Dopamine (DA) is an intrarenal natriuretic hormone involved in sodium homeostasis, but the regulation of renal dopaminergic tonus is unclear. We evaluated different pathways for elevating DA tonus to determine which are important for the ability of the kidney to produce natriuresis and studied the accompanying effects on regional renal blood flow and oxygen tension. Thus, we compared the effects of a catechol-O-methyl transferase (COMT)-inhibitor, an unspecific monoamine oxidase (MAO)-inhibitor, a D1-like receptor agonist and a DA precursor in anaesthetized rats. Sodium excretion increased sixfold after COMT inhibition, eightfold after administration of the D1-like agonist, whereas it was similar to control after MAO inhibition and infusion of DA precursor. Urinary dopamine excretion increased 42% by COMT inhibition, 55% by MAO inhibition and 12-fold after DA precursor, but remained unchanged after infusion of the D1-like agonist. The D1-like receptor agonist led to a 38% increase in the cortical blood flow and a 21% increase in outer medullary blood flow. Regional renal blood flow was unaffected by all other treatments. Cortical and outer medullary oxygen tension was unaffected in all treatment groups. To conclude, the natriuretic and haemodynamic properties of an elevation in DA tonus depends on the route by which the elevation occurred. Systemic administration of a D1-like receptor agonist, results in a natriuretic response which, as opposed to the natriuresis seen after COMT inhibition, coincides with an increase in renal cortical and outer medullary blood flow. Precursor delivery or MAO inhibition did not change neither urinary sodium excretion nor renal blood flow.

Transient glomerular hyperfiltration in the streptozotocin-diabetic Wistar Furth rat.

The glomerular hemodynamic response to streptozotocin (STZ)-induced experimental diabetes differs depending on metabolic control and rat strain used. The present study characterize the glomerular filtration rate (GFR) and other renal parameters, weekly up to eight weeks of diabetes in STZ-diabetic Wistar Furth rats. The STZ-treated rats became diabetic within 24 h after treatment and retained a blood glucose concentration of 20-25 mmol/l throughout the experimental period. The GFR was transiently increased during the first 3-5 weeks after induction of diabetes, but thereafter did not differ from control animals. The renal weight increased by approximately 50% during the first week after induction of diabetes, thereafter no further increase in weight occurred. The urinary flow rate and urinary osmolar excretion were approximately 10 times higher in diabetic animals when compared to non-diabetic animals. Although they remained markedly higher than in non-diabetic animals, both the urinary flow rate and the urinary osmolar excretion peaked after 3 weeks of diabetes and thereafter tended to decrease. The urinary sodium and potassium excretions did not differ between non-diabetic and diabetic animals. We conclude that the transient increase in the GFR seen in the human disease, occurs in Wistar Furth rats, which is in contrast to a majority of other rat strains, where the GFR is persistently increased.

The effect of dopamine receptor blockade on natriuresis is dependent on the degree of hypervolemia.

A number of different physiological factors and systems have been suggested to be responsible for the natriuretic effect following acute isotonic volume expansion (VE). The variation in suggestions may depend on the prevailing status of the systems governing fluid and electrolyte balance before VE, on the expansion medium and on the rate and degree of VE. A study was performed to determine whether the previously documented attenuating effect of dopamine receptor blockade on natriuresis induced by VE is dependent on the degree of hypervolemia. Anesthetized rats were pretreated with the dopamine receptor blockers haloperidol (1 mg.kg-1 body weight, i.p.), SCH 23390 (30 micrograms.hr-1.kg-1 i.v.) or vehicle and then subjected to VE at 2, 5 or 10% of body weight per hour. VE at 2, 5 and 10% increased sodium excretion in vehicle-pretreated animals 6-, 29- and 130-fold, respectively. In the haloperidol-pretreated animals the natriuretic response (accumulated sodium excretion) to VE was attenuated by 67% (P less than 0.05), 46% (P less than 0.05) and 22% (NS) at the three degrees of expansion, respectively. The corresponding attenuation in SCH 23390-treated animals were 60% (P less than 0.05), 56% (P less than 0.05) and 19% (NS), respectively. The gradual decrease in attenuation indicates that at varying degrees of hypervolemia, different physiological systems contribute differently to the renal natriuretic response. The dopamine system seems to be relatively more important in promoting natriuresis at the lower (physiological) range of hypervolemia whereas in the high range other factors have a greater impact.

Post-ischaemic administration of hyperosmolar mannitol enhances erythrocyte trapping in outer medullary vasculature in the rat kidney.

Mannitol is widely used as a therapeutic agent in the management of acute renal failure. We sought to determine whether mannitol influences the trapping of red blood cells (RBCs) in renal microvasculature, as measured from the distribution of 51Cr-labelled RBCs, in the rat kidney after ischaemia. The results indicate that administration of hyperosmolar mannitol after an ischaemic insult increases RBC trapping in the outer renal medulla in a dose-dependent manner. This was found to occur even though parameters of nephron function were unaffected or even improved.

CNS-induced natriuresis during dopamine receptor blockade. Further support for the existence of, at least, two separate natriuretic hormonal systems.

Intracerebroventricular (ICV) stimulation with hypertonic sodium chloride solutions has previously shown indications to stimulate the release of a blood-borne natriuretic factor. Sodium excretion in this situation increases in the order of 10-20 times. Acute isotonic volume expansion has shown to be a potent stimulus for endogenous release of the atrial natriuretic factor (ANF). It has also been demonstrated that the natriuretic response to both volume expansion and exogenously applied ANF can be attenuated by the dopamine receptor blocker haloperidol. The present study was performed to investigate if the natriuretic response to ICV stimulation also could be attenuated with haloperidol, thus indicating similar effector mechanisms as for ANF. A first group of anaesthetized animals was, therefore, pre-treated with haloperidol (H) and then ICV stimulated (H-ICV). A second group of animals was subjected to acute isotonic volume expansion (VE, 2% b.w.h.-1) to evoke the documented ANF release. In a third group of animals pre-treatment with haloperidol was followed by volume expansion (H-VE). In the H-ICV group there was a more than 30-fold increase in sodium excretion, due to an increase both in urine flow rate (more than sixfold) and in the urinary concentration of sodium (more than fourfold). Potassium excretion increased more than eightfold, urine osmolality was unchanged, and blood pressure increased by 7%. In the VE group sodium excretion increased more than 18-fold, consequent to large increases in urine flow rate (more than 23-fold), while the urinary concentration of sodium tended to decrease. Potassium excretion increased more than threefold, urine osmolality decreased by 88%, and blood pressure was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

The dopamine receptor antagonist haloperidol blocks natriuretic but not hypotensive effects of the atrial natriuretic factor.

Studies were performed on anesthetized male Münich-Wistar rats to investigate the influence of the dopamine (DA) receptor antagonist haloperidol on the natriuretic response to infusion of a synthetic atrial natriuretic factor. The whole kidney glomerular filtration rate (GFR), urinary excretion of electrolytes, and arterial blood pressure (BP) were therefore measured in groups of animals pretreated with haloperidol or vehicle and given a continuous intravenous infusion of atrial natriuretic peptide (ANP; 28 amino acids). Forty-five minutes of ANP infusion at 10 micrograms h-1 kg-1 body wt did not increase GFR (change from 1.14 +/- 0.08 to 1.15 +/- 0.05 ml min-1 g-1 kidney wt). Sodium excretion (UNaV) increased more than four-fold from 0.037 +/- 0.008 to 0.165 +/- 0.070 mumol min-1 g-1 kidney wt (P less than 0.01). Potassium excretion (UKV) increased by 86% (P less than 0.001) and the urine flow rate (V) increased transiently by 63% (P less than 0.05) and did not differ from the control value during the last 15 min of ANP infusion. The urinary sodium concentration (UNa) increased almost three-fold, while BP decreased by 14%. There was no change in urine osmolality. In animals pretreated with haloperidol (1 mg kg-1 body wt), 45 min of ANP infusion did not significantly alter GFR (from 1.10 +/- 0.08 to 0.98 +/- 0.09 ml min-1 g-1 kidney wt). The UNaV did not increase significantly (change from 0.026 +/- 0.006 to 0.030 +/- 0.009 mumol min-1 g-1 kidney wt). The UKV was not elevated by ANP infusion.(ABSTRACT TRUNCATED AT 250 WORDS)