Renal Blood Flow Rate Research Articles

CHRONIC BLOCKADE OF ENDOGENOUS FORMATION OF HYDROGEN SULFIDE CAUSED INCREASE IN SYSTEMIC BLOOD PRESSURE IN RATS

Hydrogen sulfide (H2S), an endogenous vasodilator, is produced by two enzymes; cystathionine γ‐lyase (CSE) and cystathionine β‐synthase (CBS). In this study, the effects of chronic inhibition of CSE by DL‐propargylglycine (37.5 mg/kg/day; ip) and CBS by aminoxyacetic acid (8.8 mg/kg/day; ip) given either alone or in combination for 4 weeks on systemic blood pressure (SBP) and renal function were examined in rats (n=6 in each group). Prior to the start and then every 7th day during treatment period, SBP was measured by tail‐cuff method and 24 hr urine collections were made using metabolic cages. Urinary excretion rate of sulfate (USV; marker for endogenous H2S level) was determined by a colorimetric assay. At the end of treatment period, rats were subjected to acute experiments under anesthesia for determination of renal blood flow (RBF; Transonic flow‐probe) and glomerular filtration rate (GFR; inulin clearance). Compared to vehicle treated group, only the combined therapy group showed a decrease in USV (553±71 vs 248±50 nmol/24hr) and an increase in mean SBP (107±3 vs 130±2 mmHg) with its consequent increase in sodium excretion (4±1 vs 13±3 mmol/24hr). This group with combined therapy also showed a decrease in RBF (7±0.4 vs 4±0.3 mL/min/g) but not appreciably in GFR (1.0±0.1 vs 0.9±0.03 mL/min/g). These data suggest that a decrease in endogenous H2S production exerts direct vascular effect leading to an increase in SBP.

RENAL VASOCONSTRICTION AND NATRIURESIS INDUCED BY TUMOR NECROSIS FACTOR (TNF)‐α ARE MEDIATED BY TNF RECEPTOR TYPE 1

Infusion of TNF‐α exerts renal vasoconstriction as well as natriuresis in mice. To define the receptor subtypes involved in these renal vascular and tubular actions of TNF‐α, experiments were conducted to assess the responses to human recombinant TNF‐α (0.33ng/min/g BW; i.v. infusion for 75 min) in gene knockout mice for either TNF receptor type 1 (TNFR1KO; n=6) or type 2 (TNFR2KO; n=6) and compared these results with those obtained in corresponding wild type (WT; C57BL6; n=6) mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearances respectively. As reported previously, TNF‐α infusion in WT mice resulted in decreases of 20±5% (P<0.03) in RBF, 40±2% (P<0.003) in GFR as well as increases in 83±27% (0.05>P>0.01) in urine flow (V) and 363±104% (P<0.05) in sodium excretion (UNaV). These responses are completely absent in TNFR1KO mice. TNF‐α infusion in TNFR1KO mice resulted in non‐significant changes in renal parameters (RBF; 8±22%; GFR, −18±14%; V, 15±16%; UNaV, −47±12%). However, TNF‐α infusion in TNFR2KO mice showed similar changes in renal parameters as observed those in the WT mice. The responses in TNFR2KO mice are as follows: RBF; −22±10 % (0.05>P>0.01); GFR, −36±7% (P<0.002); V, 91±19% (P<0.007); UNaV, 327±70% (P<0.01). These data demonstrate that TNF receptor type 1, not the type 2, is involved in mediating acute renal vascular and tubular actions of TNF‐α.

Untersuchung von selbstnavigierenden MR-Sequenzen für die Perfusionsbildgebung der Nieren

Due to the worldwide increasing number of cases of chronic kidney diseases renal imaging – as a non-invasive technique in magnetic resonance imaging – has become a very important tool for an early diagnosis of probable insufficiencies and malfunction. Especially, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) provides a technique to derive physiological parameters like renal blood flow or glomerular filtration rate. Similar to the entire field of abdominal imaging, the major problems are motion artifacts that primarily arise from the patient's respiration. The self-navigating BLADE-sequence with a post processing motion correction is an approach that does not require breath holding and is therefore also easily applicable to patients who are not able to undergo multiple breath hold examinations. In this work, a T 1-weighted BLADE-sequence was optimized to demonstrate the feasibility of this technique to perfusion imaging. The number of phase-encoding lines of one BLADE has a direct impact on the reduction of motion artifacts. In comparison to standard DCE-MRI sequences, the developed BLADE-sequence with optimized number of phase encoding lines could significantly reduce motion artifacts. A quantitative analysis revealed that up to a 50% displacement of the kidneys could be corrected. Therefore, it was demonstrated that dynamic motion corrected measurements without the need of a breath hold-technique are feasible.

Renal and Anti-Aldosterone Actions of Vasopressin-2 Receptor Antagonism and B-Type Natriuretic Peptide in Experimental Heart Failure

Hemodynamic and neurohumoral function can affect the efficacy of diuretic therapy in congestive heart failure. Arginine vasopressin increases water reabsorption through the V(2) receptor in the collecting duct, whereas B-type natriuretic peptide (BNP) decreases sodium reabsorption in the collecting duct. We hypothesized that combining BNP to the V(2)-receptor antagonist tolvaptan (TLV) would enhance renal excretory function by augmenting sodium excretion together with aquaresis without adversely affecting renal hemodynamics in experimental congestive heart failure. Congestive heart failure was induced in 3 groups (n=6 per group) of dogs by tachypacing. A acute experiment was done after 10 days. After baseline measurements, study groups received a 0.1 mg/kg IV bolus of TLV alone (TLV), TLV in combination with BNP (TLV+BNP; 50 ng/[kg . min]), or BNP alone (BNP). Mean arterial pressure increased with TLV, remained unchanged with TLV+BNP, and decreased with BNP (+5+/-1mm Hg versus -1+/-1 mm Hg versus -15+/-1 mm Hg; P<0.05). Renal blood flow and glomerular filtration rate were preserved with all regimens. Urine flow increased in all 3 groups but significantly more so with TLV+BNP (TLV: +0.4+/-0.1 mL/min versus TLV+BNP: +2.4+/-0.5 mL/min versus BNP: +0.8+/-0.3 mL/min; P<0.05). Only TLV+BNP and BNP were natriuretic (P<0.05), whereas only TLV and TLV+BNP increased electrolyte-free water excretion (P<0.05). Compared with TLV alone, TLV+BNP prevented an increase in aldosterone (P<0.05). Coadministration of TLV and BNP in experimental HF resulted in a beneficial profile of renal, neurohumoral, and hemodynamic actions, specifically potent diuresis with natriuresis, neutral effect on mean arterial pressure, and lack of aldosterone activation.

Effects of Supplemental Recombinant Bovine Somatotropin (rbST) and Cooling with Misters and Fans on Renal Function in Relation to Regulation of Body Fluids in Different Stages of Lactation in Crossbred Holstein Cattle

The aim of this study was to investigate the effect of supplemental recombinant bovine somatotropin (rbST) and cooling with misters and fans on renal function in relation to regulation of body fluids in different stages of lactation in crossbred Holstein cattle. Ten, 87.5% crossbred Holstein cattle were divided into two groups of 5 animals each, housing in a normal shaded barn (NS) and in a shaded barn with a mister-fans cooling system (MF). The experiment in each group was divided into 3 phases, early- (Day 75 postpartum), mid- (Day 135 postpartum), and late stage of lactation (Day 195 postpartum). The pre-treatment study was conducted on the starting day of each stage of lactation and the treatment study was performed after the end of the pre-treatment, during which the animal was injected with 500 mg of rbST (POSILAC) every 14 days for three times. During the study, ambient temperature at the hottest period daily in the MF barn was significantly lower, while relative humidity was higher than that of the NS barn. The temperature humidity index (THI) in both barns ranged from 79-85 throughout the periods of study. Cows in the MF barn showed a lower rectal temperature and respiration rate as compared with cows in the NS barn. The effect of rbST administration increased both rectal temperature and respiration rates of cows housed in either the NS or MF barn. Milk yield significantly increased in cows treated with rbST in all stages of lactation. Increases in mammary blood flow, accompanied by increases of total body water (TBW), extracellular fluid (ECF), blood volume (BV) and plasma volume (PV), were observed in both groups of cows receiving rbST in all stages of lactation. No alterations of renal blood flow and glomerular filtration rate were observed in cows receiving rbST, but decreases in urinary excretion and fractional excretion of sodium, potassium and chloride ions appeared to correlate with reduction in the rate of urine flow and osmolar clearance during rbST administration. These results suggest that the effect of rbST supplementation to cows housed either in NS or MF barns on body fluid volume expansion is attributable to changes in the rate of electrolyte excretion by the kidney. The increased availability of renal tubular reabsorption of sodium, potassium and chloride ions during rbST treatment was a major factor in retaining body water through its colligative properties in exerting formation of an osmotic force mechanism.

Polymerized type I collagen reduces chronic cyclosporine nephrotoxicity

Polymerized type I collagen (P-collagen) has been successfully used to reduce human hypertrophic scars due to its anti-fibrotic and anti-inflammatory properties. We therefore carried out a study to determine if P-collagen reduces functional and structural injury in chronic cyclosporine [cyclosporine A (CsA)] nephropathy. Four groups of six male Wistar rats fed with a low sodium diet were treated with vehicle, P-collagen (0.8 mg/day, i.p.), CsA (15 mg/kg) or CsA + P-collagen for 15 days. Mean arterial pressure, renal blood flow and glomerular filtration rate were measured in all groups. Structural injury such as arteriolopathy, tubulo-interstitial fibrosis (TI-fibrosis) and positive apoptotic cells were quantified. The mRNA expression levels of transforming growth factor-beta (TGF-beta), kidney injury molecule (Kim-1), alpha-smooth muscle actin (alpha-SMA), glutathione peroxidase, catalase and Cu/Zn superoxide dismutase (SOD) as well as MnSOD were assessed. Antioxidant enzyme activity, renal lipoperoxidation and urinary excretion of oxygen peroxide (UH(2)O(2)V) were determined. Cyclosporine produced renal dysfunction and induced the development of arteriolopathy, TI-fibrosis and tubular apoptosis. These alterations were associated with increases in TGF-beta, Kim-1 and alpha-SMA mRNA levels as well as with a significant increase of oxidative stress and a reduction of SOD activity. P-Collagen partially ameliorated CsA-induced renal dysfunction and structural injury and prevented both tubular apoptosis and increased oxidative stress. This renoprotective effect was found to be associated with a reduction of TGF-beta, Kim-1 and alpha-SMA mRNA levels. This study has therefore demonstrated that P-collagen appears to have anti-fibrotic and anti-apoptotic properties and highlights the possibility that the compound might be useful in a strategy to reduce chronic CsA nephrotoxicity.

Early and prominent alterations in hemodynamics, signaling, and gene expression following renal ischemia in sickle cell disease

Acute ischemic insults to the kidney are recognized complications of human sickle cell disease (SCD). The present study analyzed in a transgenic SCD murine model the early renal response to acute ischemia. Renal hemodynamics were profoundly impaired following ischemia in sickle mice compared with wild-type mice: glomerular filtration rate, along with renal plasma flow and blood flow rates, were markedly reduced, while renal vascular resistances were increased more than threefold in sickle mice following ischemia. In addition to these changes in renal hemodynamics, there were profound disturbances in renal signaling processes: phosphorylation of members of the MAPK and Akt signaling proteins occurred in the kidney in wild-type mice after ischemia, whereas such phosphorylation did not occur in the kidney in sickle mice after ischemia. ATP content in the postischemic kidney in sickle mice was less than half that observed in wild-type mice. Examination of the expression of candidate genes uncovered changes that may predispose to increased sensitivity of the kidney in sickle mice to ischemia: increased expression of inducible nitric oxide synthase and decreased expression of endothelial nitric oxide synthase, and increased expression of TNF-alpha. Inducibility of anti-inflammatory, cytoprotective genes, such as heme oxygenase-1 and IL-10, was not impaired in sickle mice after ischemia. We conclude that the kidney in SCD is remarkably vulnerable to acute ischemic insults. We speculate that such sensitivity of the kidney to ischemia in SCD may underlie the occurrence of acute kidney injury in patients with SCD and may set the stage for the emergence of chronic kidney disease in SCD.

The renal vascular response to diabetes

Diabetes mellitus is the primary cause of end-stage renal disease, yet the mechanisms underlying diabetic nephropathy remain ill-defined. The widely accepted opinion holds that events occurring early during the course of diabetes engender the eventual decline in renal function. This review will summarize recent advances (published January 2008 through June 2009) regarding the renal vascular and glomerular functional changes that occur during the early stage of diabetes. Reduced C-peptide levels and increased cyclooxygenase-2 activity both seem to promote diabetic hyperfiltration, presumably via effects on afferent arteriolar tone. In addition, exaggerated tonic influences of K+ channels on afferent arteriolar function likely act in concert with impaired Ca2+ influx responses to changes in membrane potential to promote vasodilation. Mechanisms underlying these changes remain largely speculative. Diabetes may also alter autoregulation of renal blood flow and glomerular filtration rate, as well as provoke afferent arteriolar dilation secondary to alterations in proximal tubular reabsorption; however, conflicting evidence continues to flood the literature concerning these events. New evidence has expanded our appreciation of the complexity of events that promote preglomerular vasodilation during the early stage of diabetes; however, it seems that the more we know, the less we understand.

COMP-Angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury

During sepsis endothelial dysfunction is an important pathogenetic mechanism in acute kidney injury (AKI). Lipopolysaccharide (LPS)-induced endotoxemia is associated with renal hemodynamic changes such as alterations of renal blood flow (RBF), vascular resistance, and glomerular filtration rate. We used adenoviral delivery of an engineered variant of native angiopoietin-1 (COMP-angiopoietin-1) containing anti-inflammatory and anti-permeability functions, to determine if regulation of renal endothelial cell dysfunction may have a beneficial role in preventing AKI during LPS-induced endotoxemia in mice. This treatment prevented the endotoxin-induced decrease of RBF and mean arterial pressure while improving glomerular filtration rate. Treatment also mitigated the effects of LPS on renal intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 protein expression, the number of ER-HR3-positive macrophages that infiltrated the kidney, serum nitrate/nitrite levels, renal inducible nitric oxide synthase protein expression, the induction of tubular epithelial reactive oxygen and nitrogen species, and renal microvascular permeability. Our findings show that COMP-angiopoietin-1, an endothelium-oriented therapeutic agent, protects against AKI caused by endotoxemia.

The renal renin-angiotensin system

The renin-angiotensin system (RAS) is a critical regulator of sodium balance, extracellular fluid volume, vascular resistance, and, ultimately, arterial blood pressure. In the kidney, angiotensin II exerts its effects to conserve salt and water through a combination of the hemodynamic control of renal blood flow and glomerular filtration rate and tubular epithelial cell sodium chloride and water transport mechanisms. Pharmacological inhibition of the actions of the RAS are widely used in the treatment of patients with hypertension, congestive heart failure, left ventricular dysfunction, pulmonary and systemic edema, diabetic nephropathy, cirrhosis of the liver, scleroderma, and migraines. Therefore, a thorough understanding of the influences of the RAS on normal renal physiology is of major importance for first-year medical students.

Role of renal microcirculation in experimental renovascular disease

Renal artery stenosis (RAS) causes renal injury partly via microvascular (MV) endothelial dysfunction and damage. Vascular endothelial growth factor (VEGF) is crucial for preservation of microvasculature and promotes vascular proliferation and endothelial repair. We have previously shown that MV rarefaction is associated with decreased VEGF in the kidney exposed to chronic RAS, accompanied by deteriorated renal function and fibrosis. We hypothesized that preserving the renal microcirculation in the stenotic kidney will halt the progression of renal damage. Unilateral RAS was induced in 16 pigs. In eight, VEGF (0.05 micrograms/kg) was infused intra-renally at the onset of RAS. After 6 weeks, single-kidney haemodynamics and function were assessed using in vivo multi-detector computed tomography (CT). Renal microvessels, angiogenic pathways and morphology were investigated ex vivo using micro-CT, real-time PCR and histology. Blood pressure and degree of RAS was similar in RAS and RAS + VEGF pigs. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in RAS compared to Normal (221.1 +/- 46.5 and 29.9 +/- 3.8 vs. 522.5 +/- 60.9 and 49.3 +/- 3.4 mL/min, respectively, P < 0.05), accompanied by decreased cortical MV density and increased renal fibrosis. Pre-emptive administration of VEGF preserved MV architecture, attenuated fibrosis and normalized RBF and GFR (510.8 +/- 50.9 and 39.9.1 +/- 4.1 mL/min, P = not significant vs. Normal). This study underscores the importance of the renal microcirculation in renovascular disease. Intra-renal administration of VEGF preserved renal MV architecture and function of the stenotic kidney, which in turn preserved renal haemodynamics and function and decreased renal fibrosis. These observations suggest that preventing renal MV loss may be a potential target for therapeutic approaches for patients with chronic renovascular disease.

Abstract 5265: Alternatively Spliced B-Type Natriuretic Peptide (ASBNP) is a Renal Selective Natriuretic and Diuretic Peptide Without Hypotensive Properties

Background: B-type natriuretic peptide (BNP1–32) is a 32- amino acid cardiac peptide secreted in response to cardiac stress and plays an important compensatory role in cardiorenal homeostasis. Studies have recently reported that a mRNA encoding an alternatively spliced variant of BNP (ASBNP) exists in the human heart and like BNP1–32 is increased in the failing heart. While ASBNP and BNP1–32 have identical ring structures and amino termini, ASBNP and BNP1–32 differ in their carboxy terminus (34 vs. 6 amino acids, respectively). Studies have also reported that ASBNP activates cGMP, the second messenger of BNP1–32, in isolated glomeruli but not in endothelial cells. Also, unlike BNP1–32 ASBNP does not vasorelax isolated arteries or veins. The cardiorenal actions in vivo of ASBNP are unknown. We hypothesized that ASBNP in vivo would have selective renal actions yet as suggested by studies in isolated vessels would be devoid of blood pressure effects. Methods: We therefore determined for the first time the cardiorenal actions of three subsequent intravenous doses of ASBNP (10, 50, and 150 pmol/kg/min) in 5 healthy canines in an acute study under anesthesia in 30-minute clearances at baseline, during, and following infusion. Values provided are mean±SEM for baseline vs. 150 pmol/kg/min. *p&lt;0.05. Results: ASBNP dose-dependently increased plasma levels of cGMP (8.6±1.0 vs. 11.5±1.3* pmol/mL), and the same was true for urinary cGMP excretion (878±191 vs. 2028±551* pmol/min). Mean arterial pressure (p=0.83) and heart rate (p=0.43) remained unchanged. Urine flow increased (0.38±0.05 vs. 1.32±0.20* mL/min) as did urinary sodium excretion (38±15 vs. 133±38* μ Eq/min). Renal blood flow (p=0.51) and glomerular filtration rate (p=0.99) remained unchanged. BNP-immunoreactivity as measured by the Biosite BNP assay increased (5±4 vs. 3807±573* pg/mL). Conclusion: ASBNP, an alternatively spliced form of BNP produced in the human heart, activates cGMP and has diuretic and natriuretic actions but is without blood pressure lowering actions. Thus, ASBNP represents a novel renal selective, non-hypotensive, natriuretic, and diuretic peptide.

The chemokine monocyte chemoattractant protein-1 contributes to renal dysfunction in swine renovascular hypertension

Renal artery stenosis (RAS) causes renovascular hypertension and renal damage, which may result from tissue inflammation. We have previously shown that the kidney in RAS exhibits increased expression of monocyte chemoattractant protein (MCP)-1, but its contribution to renal injury remained unknown. This study tested the hypothesis that MCP-1 contributes to renal injury and dysfunction in the stenotic kidney. Kidney hemodynamics, function, and endothelial function were quantified in pigs after 10 weeks of experimental RAS (n = 7), RAS supplemented with the MCP-1 inhibitor bindarit (RAS + bindarit, 50 mg/kg/day orally, n = 6), and normal controls (n = 8). Renal inflammation was assessed by the immunoreactivity of MCP-1, its receptor chemotactic cytokine receptor 2, and NFkappaB, and oxidative stress by nicotinamide adenine dinucleotide phosphate-oxidase expression and in-situ superoxide production. Renal microvascular density was evaluated by micro-CT and fibrosis by trichrome staining, collagen-I immunostaining, and hydroxyproline content. After 10 weeks of RAS, blood pressure was similarly elevated in RAS and RAS + bindarit. Compared with normal controls, stenotic RAS kidneys had decreased renal blood flow (5.4 +/- 1.6 vs. 11.4 +/- 1.0 ml/min/kg, P < 0.05) and glomerular filtration rate and impaired endothelial function, which were significantly improved in bindarit-treated RAS pigs (to 8.4 +/- 0.8 ml/min/kg, P < 0.05 vs. RAS). Furthermore, bindarit markedly decreased tubulointerstitial (but not vascular) oxidative stress, inflammation, and fibrosis, and slightly increased renal microvascular density. The impaired renovascular endothelial function, increased oxidative-stress, and fibrosis in the contralateral kidney were also improved by bindarit. MCP-1 contributes to functional and structural impairment in the kidney in RAS, mainly in the tubulointerstitial compartment. Its inhibition confers renoprotective effects by blunting renal inflammation and thereby preserving the kidney in chronic RAS.

Fetal development and renal function in adult rats prenatally subjected to sodium overload

The aims of this study were (1) to evaluate two factors that affect fetal development--placental oxidative stress (Ox) and plasma volume (PV)--in dams with sodium overload and (2) to correlate possible alterations in these factors with subsequent modifications in the renal function of adult offspring. Wistar dams were maintained on 0.17 M NaCl instead of water from 20 days before mating until either the twentieth pregnancy day/parturition or weaning. Colorimetric methods were used to measure Ox in maternal and offspring tissues, PV, 24-h urinary protein (U(Prot24 h)) and serum triacylglycerols (TG) and cholesterol (Chol). Renal hemodynamics was evaluated in the offspring at 90 days of age using a blood pressure transducer, a flow probe and inulin clearance to measure mean arterial pressure (MAP), renal blood flow and glomerular filtration rate (GFR), respectively. The number of nephrons (NN) was counted in kidney suspensions. Dams showed unchanged PV, placental Ox and fetal weight but increased U(Prot24 h) (150%, P < 0.05). Prenatally sodium-overloaded pups showed increased U(Prot24 h) (45%, P < 0.05) but unchanged MAP, renal hemodynamics, NN and kidney Ox. Prenatally and postnatally sodium-overloaded rats showed increased U(Prot24 h) (27%, P < 0.05) and kidney Ox (44%, P < 0.05), reduced GFR (12%, P < 0.05), increased PV (26%, P < 0.05) and unchanged MAP and NN. The TG increased in both groups of treated offspring (21%, P < 0.05), whereas Chol increased only in the postnatally sodium-overloaded group. We conclude that salt overload from the prenatal stage until weaning leads to alterations in lipid metabolism and in the renal function of the pups, which are additional to those alterations seen in rats only overloaded prenatally.

To use or not to use: the dilemma of NSAIDs and craniotomy

To use or not to use: the dilemma of NSAIDs and craniotomy

Exercise-Associated Hyponatremia

Disorders of serum sodium occur commonly in athletes participating in endurance sports. The most life-threatening of these is hyponatremia, which can occur in as many as 2% to 7% of participants. Exercise-associated hyponatremia (EAH) is caused by a combination of excessive water or hypotonic fluid intake as well as high levels of arginine vasopressin, which limits the ability of the kidney to excrete water. Other factors in the pathogenesis of EAH include sweat sodium loss, inability to mobilize exchangeable sodium stores, metabolic water production, and impaired renal blood flow and glomerular filtration rate. Most cases of EAH lead to minimal or absent complications and do not require specific therapy other than close monitoring and fluid restriction. However, a small number of athletes may present with severe and life-threatening hyponatremia associated with cerebral edema and possibly noncardiogenic pulmonary edema. Rapid diagnosis and appropriate therapy of these athletes with hypertonic saline is required to prevent severe complications or death.

Effects of GLP-1,Exendin-4 and C-peptide on renal blood flow in rats

Objective To evaluate the effects of glucagon-like peptide-1(GLP-1),Exendin-4 and C-peptide on renal blood flow(RBF)in normoglycaemic and hyperglycaemic rats.Methods Adult male Wistar rats were divided into 4 groups and intravenously given saline(or 30%glucose,as control),GLP-1,Exendin-4 and C- peptide respectively. Mean arterial blood pressure was monitored and mierosphere technique was adopted to measure RBF and adrenal blood flow. Results Glucose administration augmented RBF significantly(P 0.05).Exendin-4 had no effect on either basal RBF or post-glucose-load RBF,but prevented the glueose-induced increase of RBF.C-peptide enhanced basal RBF(P<0.0 1),but did not affect RBF after glucose injection. Conclusion GLP-1.Exendin-4 and C-peptide exert a regulatory effect on RBF in Wistar rats.Exendin-4 prevents the increment of RBF in hyperslycaemic rats and miight be a promising agent against diabetic nephropathy. Key words: C-peptide; Glucagon-like peptide-1; Exendin-4; Microsphere technique; Renal blood flow

Histone deacetylase blockade improves renal function and attenuates oxidative stress in rats with cisplatin‐induced acute renal failure

Histone deacetylase (HDAC) inhibition has been shown to prevent cytokine induction and to modulate renal disease in rodent models. We tested the hypothesis that HDAC inhibition would improve various renal and oxidative stress parameters in cisplatin (CDDP)‐induced acute renal failure (ARF). 15‐week old male Sprague‐Dawley rats (n=4 per group) were treated with the HDAC inhibitor, valproic acid (VPA; 300 mg/kg, s.c.), or vehicle, for 1 day prior to and 5 days following induction of ARF with a single 6 mg/kg injection of CDDP (or saline vehicle). At the end of 6 days, anesthetized rats underwent acute renal experiments to determine renal blood flow (RBF) and glomerular filtration rate (GFR) using PAH and inulin clearance techniques, respectively. Rats were sacrificed and kidneys removed; renal cortices were isolated for measurement of tissue and mitochondrial free radical levels using electron paramagnetic resonance spectroscopy. Tissue mRNA and protein levels of HDAC and oxidative stress genes were determined using real‐time RT‐PCR and western blot, respectively. No significant changes in mean arterial pressure (MAP) were noted among groups. VPA treatment improved RBF and GFR (p&lt;0.05) and attenuated the higher levels of total tissue and mitochondrial ROS and tissue superoxide in ARF rats. VPA treatment also significantly decreased tissue mRNA and protein expression levels of HDAC and oxidative stress genes, and normalized ATP production and ADP/ATP ratio in rats with ARF. These findings suggest that inhibition of class I HDACs with VPA improves the renal oxidative stress and tissue and mitochondrial injury that accompany CDDP‐induced ARF. Grant support: NIH grant RO1HL080544‐01 for Dr. Joseph Francis.

Impaired pressure‐natriuresis relationship precedes the development of hypertension in Cyp1a1‐Ren‐2 transgenic rats

ObjectiveThe present study was performed to characterize the autoregulatory efficiency of renal blood flow (RBF) and glomerular filtration rate (GFR) and the pressure‐natriuresis relationship in transgenic rats with inducible hypertension (Cyp1a1‐Ren‐2 rats).MethodsThe renin gene was induced in Cyp1a1‐Ren‐2 rats trough dietary administration of the natural xenobiotic indole‐3‐carbinol (I3C, 0.3 %) for 12 hours. Non‐induced rats served as controls. Anesthetized rats were prepared for renal function studies and an aortic clamp was placed on the aorta to regulate the level of renal arterial pressure. ANG II levels were measured by radioimmunoassay.ResultsAdministration of I3C resulted in progressive increases in ANG II levels as compared with non‐induced rats. I3C‐induction for 12 hours did not cause significant changes in blood pressure as compared with non‐induced rats. 12 hours I3C‐induction caused an impairment of the autoregulatory efficiency of RBF and GFR and of the pressure‐natriuresis relationship as compared with non‐induced rats.ConclusionsOur findings indicate that an impairment of the pressure‐natriuresis mechanism precedes the development of ANG II‐dependent hypertension in Cyp1a1‐Ren‐2 transgenic rats.

Tumor necrosis factor‐alpha (TNF‐α) induced natriuresis is prevented by blockade of distal tubular sodium transport in mice.

We demonstrated earlier that acute TNF‐α administration in mice resulted in marked natriuresis despite its induction of renal vasoconstriction and hypofiltration. To examine whether this natriuresis is caused by a direct inhibitory action of TNF‐α on epithelial sodium transport, we assessed the renal responses to TNF‐α infusion (0.3 ng/min/g; i.v.) in anesthetized mice (n=6) pretreated with combined administration of amiloride (AM; 17 μg/kg/min; i.v.) and bendroflumethiazide (BZ; 2.8 μg/kg/min, i.v.) that would block distal tubular sodium transport. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearances. TNF‐α infusion in AM+BZ pretreated mice caused reductions of 35+8% in RBF (10.2±1.7 to 6.5±1.2 mL/min/g) and 43±6% in GFR (1.02±0.1 to 0.60±0.8 mL/min/g) with a slight decrease in mean arterial pressure (87±4 to 79+3 mmHg) which were similar to those observed in non‐treated mice reported earlier. However, contrary to the natriuretic response observed in non‐treated mice in our earlier study, TNF‐α in these AM+BZ pretreated mice resulted in a marked reduction of 64+9% in sodium excretion (4.4±0.3 to 1.5±0.3 μmol/min/g) with no significant change in fractional excretion of sodium (3.1±0.2 to 2.2±0.7%). These data suggest that TNF‐α induced natriuretic response results from its direct inhibitory action on distal tubular sodium transport.