Reduction In Renal Plasma Flow Research Articles

544 Interleukin-6 protects renal dysfunction in mouse models of hypertension and salt-sensitive hypertension

OBJECTIVES/GOALS: We are investigating the role of IL-6 in regulating renal function by measuring mean arterial pressure (MAP), renal plasma flow (RPF) and glomerular filtration rate (GFR) in wild type (WT) and IL-6-knockout (KO) mice in established mouse models of angiotensin II (AII)-dependent- hypertension and -salt-sensitive hypertension. METHODS/STUDY POPULATION: Twelve-week-old male WT and KO mice on the C57BL6 background strain were infused with vehicle (V; saline) or angiotensin II (AII; 200 ng/kg/min) for 12-14 days. Half of the AII-treatment groups were maintained on a high salt (HS; 6% NaCl) diet for the duration of the experiment, while the other half of the AII treatment groups and both vehicle groups were fed normal rat chow. MAP was continuously measured by a fluid filled catheter in conscious mice for the duration of the experiment. RPF and GFR were measured on days 12-14 in anesthetized mice by the para-aminohippurate, and fluorescein isothiocynate-Inulin techniques, respectively. All data were analyzed by 2-way ANOVA; *p<0.05 vs. WT, same treatment; #p<0.05 vs.V, same genotype; ^p<0.05, AII vs. AII+HS, same genotype. RESULTS/ANTICIPATED RESULTS: MAP was 31% lower in KO vs WT mice. AII increased MAP (1.2-fold) in WT but not KO mice. HS diet magnified AII-induced increases in MAP in WT and moderately increased MAP in AII-KO mice: [MAP (mmHg): WT+V, 130±7.0; KO+V, 91.0+4.0*; WT+AII, 153±5.0#; KO+AII, 83.0±4.0*; WT+AII+HS, 150±11#; KO+AII+HS, 93.0±4.0#]. AII infusion reduced RPF in the KO but not WT mice. Addition of HS reduced RPF in WT and exacerbated AII-induced reductions in RPF in KO mice [RPF (ml/min/g): WT+V, 1.82±0.23; KO+V, 1.91+0.40; WT+AII, 3.16±0.75#; KO+AII, 1.65±0.42*; WT+AII+HS, 1.10±0.31#^; KO+AII+HS, 1.13±0.XX#^]. The HS diet reduced GFR in AII-infused KO but not WT mice [GFR (µl/min/g): WT+V, 756±XX; KO+V, 788±XX; WT+AII, 1010±63*#; KO+AII, 756±23*; WT+AII+HS, 1100±150#; KO+AII+HS: 540±210*#^]. DISCUSSION/SIGNIFICANCE: The absence of IL-6 in male mice attenuated AII- and/or AII+HS-induced increases in MAP; however, it exacerbated HS-induced reductions in RPF and GFR. These findings suggest inhibiting IL-6 has therapeutic potential as an antihypertensive but not as a renal protective agent in hypertension and salt-sensitive hypertension disease states.

The Role of Thyroid in Renovascular Function: Independent Association of Serum TSH With Renal Plasma Flow.

There are well-established interactions between the thyroid and the kidney. Thyroid hypofunction is associated with reduced renal plasma flow (RPF), and hypothyroidism is highly prevalent in chronic kidney disease; however, less is known about the thyroid-kidney axis in the euthyroid state. This work aimed to study the association of thyroid function with renovascular parameters in a well-phenotyped cohort of euthyroid normotensive and hypertensive individuals. This cross-sectional, multicenter study of the HyperPATH Consortium took place in 5 US and European academic institutions. A total of 789 individuals, aged 18 to 65 years, with serum thyrotropin (TSH) 0.4 to 5.5 mIU/L, participated; individuals with uncontrolled or secondary hypertension or on medication affecting the hypothalamus-pituitary-thyroid axis were excluded. Hemodynamic parameters including RPF, thyroid function testing, and the Thr92Ala deiodinase 2 (D2) polymorphism were assessed in the setting of a liberal and restricted salt diet. We searched for associations between thyroid function and renovascular parameters and accounted for confounding factors, such as older age, hypertension, and diabetes. Serum TSH was inversely associated with RPF assessed in the setting both of liberal and restricted salt diets. This association remained significant and independent when accounting for confounding factors, whereas free thyroxine index (fTI) and the Thr92Ala polymorphism, associated with lower D2 catalytic activity and disrupted thyroid hormone tissue availability, were not independently associated with RPF. Serum TSH remained an independent predictor of RPF on a liberal salt diet when the analysis was restricted to healthy young individuals. Serum TSH levels, but not fTI nor the Thr92Ala D2 polymorphism, were independently inversely associated with RPF in individuals of the HyperPATH Consortium. These findings suggest a direct interconnection between TSH and renovascular dynamics even with TSH within reference range, warranting further investigation.

Renal insufficiency in overt hypothyroidism

Hypothyroidism is a common endocrine disorder worldwide. In hypothyroidism, there is altered regulation of renal hemodynamics and basal metabolic rate. This hospital-based case-control study was done to evaluate the changes in uric acid level in hypothyroid subjects. This study includes 25 hypothyroid cases with age and sex-matched controls. Serum total thyroid profile was estimated by ChemiluminiscenceImmunoassay (CLIA) and uric acid by the Uricase method in fully automated Vitros 5600. The mean uric acid level is increased in hypothyroid. Triiodothyronine(T3)&Thyroxine(T4)levelof hypothyroid patients showed a significant negative correlation with uric acid with 'r' values of 0.45 and 0.51, respectively. A positive correlation was observed between Thyroid-stimulating hormone (TSH) and uric acid (p=0.22) in hypothyroid subjects. The raise in uric acid is hypothyroid subjects is due to hemodynamic changes like reduction in renal plasma flow and disordered thyroid state affects purine metabolism, leading to hyperuricemia and gout. Hence, these parameters should be monitored regularly in hypothyroid patients.

Cardiac Versus Renal Response to Volume Expansion in Preclinical Systolic Dysfunction With PDEV Inhibition and BNP

Impaired cardiorenal response to acute saline volume expansion in preclinical systolic dysfunction (PSD) may lead to symptomatic heart failure. The objective was to determine if combination phosphodiesterase-V inhibition and exogenous B-type natriuretic peptide (BNP) administration may enhance cardiorenal response. A randomized double-blinded, placebo-controlled study was conducted in 21 subjects with PSD and renal dysfunction. Pre-treatment with tadalafil and subcutaneous BNP resulted in improved cardiac function, as evidenced by improvement in ejection fraction, left atrial volume index, and left ventricular end-diastolic volume. However, there was reduced renal response with reduction in renal plasma flow, glomerular filtration rate, and urine flow. (Tadalafil and Nesiritide as Therapy in Pre-clinical HeartFailure; NCT01544998).

EFFECTS OF THE NO SYNTHASE INHIBITOR RONOPTERIN (VAS203) ON MICRO- AND MACROCIRCULATION IN HEALTHY VOLUNTEERS

Objective: The tetrahydrobiopterin-analogue VAS203, an in vivo inhibitor of predominantly the inducible nitric oxide synthase (iNOS), was developed to reduce secondary damage in patients with severe traumatic brain injury. However, its effect on micro- and macrocirculation is less well established. The aim of the present study was to characterize in detail the pharmacological effects of VAS203 on micro- and macrocirculation in humans. Design and method: In this single-centre, double-blind, randomized, placebo-controlled cross-over phase I study 16 healthy male subjects were included. A constant infusion of VAS203 (total 10 mg/kg body weight) or placebo was administered for 6 hours. After a wash-out phase of 28 days the second course with either placebo or VAS203 was applied. Renal hemodynamics were assessed with constant-infusion input-clearance technique with para-aminohippuric acid (PAH) for renal plasma flow (RPF). In addition, we assessed retinal capillary flow, as microvascular parameter by scanning laser Doppler flowmetry (SLDF) at 670 nm and used pulse wave analysis by SphygmoCorTM device for assessment of central systolic pressure, as macrovascular parameter of systemic circulation. Results: Intravenous infusion of VAS203 resulted in a reduction of RPF, but remained unchanged with placebo (Figure), resulting in a significant decrease of RPF with VAS203 compared to placebo (p < 0.0001).In contrast, mean retinal capillary flow (mirroring cerebral circulation) remained preserved at any time-point during as well as up to 2 hours after intravenous infusion of VAS203 (all p > 0.4). Compared to placebo, there was no change of brachial blood pressure due to VAS203 infusion (p > 0.2). In addition, no significant effect of VAS203 infusion on central systolic pressure was observed, indicative of no clinical meaningful effects of VAS203 on systemic circulation (p > 0.1). Conclusions: Our phase I study in humans indicate that a dose of 10 mg/kg body weight VAS203 reduces renal perfusion within a physiological range, but has no other acute effects on assessed parameters of micro- and macrocirculation.

Acute Effects of Tolvaptan on Renal Hemodynamics in Autosomal Dominant Polycystic Kidney Disease &amp;lt;br/&amp;gt;—A Randomized, Cross-Over, Double Blind, Placebo-Controlled Study of Renal Plasma Flow and Glomerular Filtration Rate

Background: Previous studies have shown that reduced renal plasma flow (RPF) may play a role in progression of renal disease in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan, a vasopressin 2 antagonist, reduces growth of total kidney volume and slows the decrease in estimated glomerular filtration rate (eGFR) in ADPKD. The purpose of this randomized, cross-over, double-blind, placebo-controlled study was to investigate if acute tolvaptan treatment increases RPF in ADPKD patients. Methods: Eighteen ADPKD patients (chronic kidney disease stages I-III) were investigated twice (min. 10 days apart) after acute treatment with either tolvaptan 60 mg or placebo. Two hours after treatment RPF and GFR were estimated by Technetium-99m diethylenetriamine penta-acetic acid (99-mTc-DTPA) renography. During the examination day, central and brachial blood pressures (BP) were measured using Mobil-O-Graph® PWA. We also measured plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensin II (p-AngII) and aldosterone (p-Aldo), urine excretion of aquaporin 2 (u-AQP2), urine output (OU), urine osmolality (u-Osm) and fractional excretion of sodium (FENa). Results: 99-mTc-DTPA renography showed a similar RPF (673 ± 262 ml/min after tolvaptan vs. 650 ± 209 ml/min after placebo, p = 0.571) and GFR (78 ± 26 ml/min after tolvaptan vs. 79 ± 21 ml/min after placebo p = 0.774) after tolvaptan and placebo treatment. P-AVP and UO increased and u-Osm decreased after tolvaptan and remained unchanged during placebo. Systolic BP tended to decrease during renography during tolvaptan. Very small or insignificant changes were seen in PRC, p-AngII and p-Aldo. Conclusions: Acute tolvaptan treatment did not change renal hemodynamics in ADPKD.

Consequences of advanced aging on renal function in chronic hyperandrogenemic female rat model: implications for aging women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine and reproductive disorder in premenopausal women, characterized by hyperandrogenemia, metabolic syndrome, and inflammation. Women who had PCOS during their reproductive years remain hyperandrogenemic after menopause. The consequence of chronic hyperandrogenemia with advanced aging has not been studied to our knowledge. We have characterized a model of hyperandrogenemia in female rats and have aged them to 22–25 months to mimic advanced aging in hyperandrogenemic women, and tested the hypothesis that chronic exposure to hyperandrogenemia with aging has a deleterious effect on renal function. Female rats were chronically implanted with dihydrotestosterone pellets (DHT 7.5 mg/90 days) that were changed every 85 days or placebo pellets, and renal function was measured by clearance methods. Aging DHT‐treated females had a threefold higher level of DHT with significantly higher body weight, mean arterial pressure, left kidney weight, proteinuria, and kidney injury molecule‐1 (KIM‐1), than did age‐matched controls. In addition, DHT‐treated‐old females had a 60% reduction in glomerular filtration rate, 40% reduction in renal plasma flow, and significant reduction in urinary nitrate and nitrite excretion (UNOxV), an index of nitric oxide production. Morphological examination of kidneys showed that old DHT‐treated females had significant focal segmental glomerulosclerosis, global sclerosis, and interstitial fibrosis compared to controls. Thus chronic hyperandrogenemia that persists into old age in females is associated with renal injury. These data suggest that women with chronic hyperandrogenemia such as in PCOS may be at increased risk for development of chronic kidney disease with advanced age.

Renovascular hypertension: Effects of mesenchymal stem cells in the contralateral hypertensive kidney in rats

ABSTRACTMesenchymal stem cells (MSC) induced neovascularization and improved renal morphology of the stenotic kidney in 2 kidneys-1 clip (2K-1C) model of renovascular hypertension. The present study evaluated the effects of MSC in the contralateral hypertensive kidney. Three weeks after left renal artery occlusion, MSC were injected into the tail vein of the 2K-1C rats. Renal function and morphology were analyzed in both kidneys. Labeled MSC were found in stenotic and contralateral kidneys. Hypertensive 2K-1C animals presented increased circulating levels of Angiotensin II (Ang II) and renin. MSC prevented the progressive increase of blood pressure and reduced circulating Ang II and renin levels. Stenotic kidney showed reduced renal plasma flow (RPF) and glomerular filtration rate (GFR), whereas the contralateral kidney had a tendency (p > 0.5) of reduction in GFR in spite of unchanged RPF. MSC treatment caused an improvement in GFR with no effect of on RPF in the stenotic kidney. Contralateral kidney showed increased diuresis and natriuresis that were even higher in MSC-treated animals, indicating that cell treatment improved the capacity of the contralateral kidney to excrete sodium. Contralateral kidney expressed higher levels of inflammatory cytokines (IL-6, TNF-α) and signs of fibrosis, which were attenuated by MSC treatment. MSC treatment improved the stenotic kidney function, and it was also beneficial to the contralateral hypertensive kidney because it improved the morphology and preserved its capacity to excrete sodium.

MP34-20 TRANSIENT RECEPTOR POTENTIAL A1 ION CHANNEL ANTAGONISM ABOLISHES INCREASED URETER IN VIVO PERISTALSIS CAUSED BY UROTHELIAL DAMAGE IN RATS

aminohippuric acid before and 1 h after sham-PCNL or the PCNL surgical procedures. RESULTS: Control pigs that did not undergo surgery showed no significant change in renal plasma flow over the experimental observation period. In contrast, a single-needle stick to access the urinary collecting system resulted in renal vasoconstriction (25% reduction in renal plasma flow, P<0.05). Single-needle access plus creation of the nephrostomy tract did not lead to a further decline in renal plasma flow. CONCLUSIONS: The renal vasoconstriction observed after PCNL surgery is largely due to the act of inserting a needle into the kidney for percutaneous access to the urinary collecting system.

Correlation of serum uric acid and serum creatinine in hypothyroidism

Background: Hypothyroidism is a progressive disorder that presents with diverse degrees of thyroid failure and metabolic consequences. Purine metabolism can be affected by disturbance in thyroid hormones, which leads to alteration in the uric acid levels, leading to hyperuricemia and subsequently causing gout. Also, hemodynamic changes occur in hypothyroidism that leads to reduction in renal plasma flow and glomerular filtration rate, which also causes increase in the levels of serum uric acid and serum creatinine. Aims and Objective: To determine whether thyroid dysfunction, subclinical and overt, has deleterious effects on renal function. Materials and Methods: This was a cross-sectional study that comprised 108 individuals (56 cases and 52 controls; 52 men and 56 women) aged between 20 and 60 years. Case group comprised suspected cases of hypothyroidism. Serum TSH, T4, T3, uric acid, and creatinine were estimated after applying inclusion and exclusion criteria. Result: Uric acid and creatinine levels were significantly elevated in case group as compared to control group (7.09 ± 0.45 and 1.52± 0.16 mg/dL versus 4.08 ± 0.25 and 0.62 ± 0.05 mg/dL, respectively; p < 0.001). There was insignificant correlation between serum uric acid and creatinine levels with hypothyroidism (r = 0.185, p = 0.172 and r = 0.082, p = 0.550). Also, there was no significant correlation between serum uric acid and creatinine levels with the age in hypothyroidism (r = 0.143; p = 0.292 and r = -20.154; p = 0.257, respectively). Conclusion: Hypothyroidism causes significant increase in serum uric acid and creatinine levels. Therefore, we would emphasize the importance of the routine evaluation of serum uric acid and creatinine levels in patients with hypothyroidism.

Abstract 295: Sodium Restriction Increases Ophthalmic Artery Systolic Velocity in Healthy Subjects

Changes in ocular blood flow occur in systemic diseases. A high peak systolic velocity (PSV) in the ophthalmic artery (OA) has been observed in diabetes mellitus and hypertension, conditions often associated with high tissue renin-angiotensin system (RAS) activity and reduced renal plasma flow (RPF). Since our group has demonstrated that sodium restriction ( a high RAS state ) is associated with a decrease in RPF which is correctable with ACE inhibition, we hypothesized that sodium restriction would result in higher ophthalmic PSV. Sixteen healthy volunteers (age 46.2±13.2, male 69%, white 75%, BMI 26±3.7) were placed on a low sodium (LS) diet (10 mmol/day) for 1 week followed by high sodium (HS) diet (200 mmol/day). Sodium balance was assessed by 24hr urine collection. BP, RPF (PAH clearance) and OA hemodynamic measurements (Multigon, NY) were made after overnight fasting and rest in the supine position. Sodium restriction did not affect BP (systolic/diastolic LS: 121/73 ± 12/7 vs HS: 122/72 ± 15/9 mmHg, mean ± SD, NS) or heart rate (69 ± 16 vs 70 ± 15/min, NS). As expected, RPF was lower on LS compared with HS (599.2 ± 89.8 vs 633.4 ± 93.5ml/min/1.73 m 2 , p=0.006). Sodium restriction was associated with higher OA peak (38.8 ± 6.4 vs 33.2 ± 6.0 cm/sec, p=0.018) and mean (19.7±2.9 vs 17.1±3.5, p=0.003) systolic velocity ( Figure ). There was no change in end-diastolic velocity (10.6±2.5 vs 9.7±2.4, p=0.266) with sodium restriction. In conclusion, sodium restriction was associated with an increase in OA peak and mean systolic velocity in healthy individuals. Further studies are required to investigate the potential relevance of our results to diabetic and hypertensive retinopathy.

Renale Sympathikusdenervation

As much as one third of patients with arterial hypertension are treatment refractory as they do not reach sufficient blood pressure control despite antihypertensive combination therapy of significant duration. In patients with therapy-resistant hypertension, the kidneys play a central role as activator of the sympathetic nervous system. Sympathetic nervous activation via efferent nerve fibers lying in the adventitia of the renal arteries leads to increased Na(+) reabsorption, increased renin secretion and reduction of renal plasma flow. Via afferent sympathetic fibers in the dorsal root of the spinal chord, the kidneys induce a further augmentation of central sympathetic nervous activity. With the method of renal sympathetic denervation (RSD) an interventional minimally invasive procedure has become available to precisely ablate afferent and efferent sympathetic nervous fibers surrounding the renal artery. Via an ablation catheter with an electrode tip and a radiofrequency generator a series of 4-6 ablation sites are administered in both renal arteries leading to denervation of the sympathetic nerve fibers while keeping the renal artery intact. Recent studies showed a significant and continuous reduction of blood pressure of 25-30mmHg systolic and 10-15mmHg diastolic for at least 2 years. Concerning the role of elevated sympathetic nervous system activity in forms of hypertension associated with other disorders, further applications of the procedure appear possible, although these are of a rather speculative nature at this time. The current mainstay of therapy-refractive hypertension is RSD, which is well supported by recent clinical data.

Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats with inducible hypertension.

In the present study, we examined the effects of soluble epoxide hydrolase (sEH) inhibition on the development of angiotensin II-dependent hypertension and on renal function in transgenic rats with inducible expression of the mouse renin gene (strain name Cyp1a1-Ren-2). Hypertension was induced in these rats by indole-3-carbinol (I3C; 0.3% in the diet) for 12 days. The sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) was given in two doses (13 or 26 mg l-1) in drinking water. Blood pressure (BP), body weight (BW) and renal excretory parameters were monitored in conscious animals during the experiment. Renal haemodynamics was assessed at the end of treatment in anaesthetized rats. I3C administration resulted in severe hypertension with a rise in systolic BP from 118 ± 2 to 202 ± 3 mmHg, a loss of BW from 266 ± 5 to 228 ± 4 g and a rise in proteinuria from 14 ± 2 to 34 ± 3 mg day-1. Both doses of c-AUCB significantly attenuated the development of hypertension (systolic BP of 181 ± 4 and 176 ± 4 mmHg, respectively), the loss in BW (256 ± 4 and 259 ± 3 g, respectively) and the degree of proteinuria (27 ± 2 and 25 ± 3 mg day-1, respectively) to a similar extent. Moreover, c-AUCB prevented the reduction in renal plasma flow (5.4 ± 0.4 vs. 4.6 ± 0.3 ml min-1 g-1) and significantly increased sodium excretion (0.84 ± 0.16 vs. 0.38 ± 0.08 μmol min-1 g-1) during I3C administration. These data suggest that the oral administration of c-AUCB displays antihypertensive effects in Ren-2 transgenic rats with inducible malignant hypertension via an improvement of renal function.

SOLUBLE EPOXIDE HYDROLASE INHIBITION IMPROVES THE RENAL FUNCTION DURING THE DEVELOPMENT OF MALIGNANT HYPERTENSION IN CYP1A1-REN-2 TRANSGENIC RATS: PP.29.172

Objective: The present study evaluated the effects of soluble epoxid hydrolyse inhibitor (sEH) on blood pressure (BP) and renal function in transgenic rats with inducible expression of mouse Ren-2 renin gene (Cyp 1a1-Ren-2). Methods: Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration of xenobiotic indole-3-carbinol (I3C, 0,3%) for 3 and 11 day. Non-induced rats served as controls. The sEH inhibitor, cis-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) was given in drinking water (1 mg/day) starting 48 hours before the induction of hypertension. Acute clearence studies were performed in c-AUCB treated and untreated anasthetized rats (n = 9–10). The blood pressure (BP) was monitored. Results: 3 and 11 day administration of I3C resulted in substantial hypertension (167 ± 3 and 188 ± 3 vs. 129 ± 2 mmHg, p < 0,001) and a marked reduction of renal plasma flow (RPF) (4,2 ± 0,3 and 4,6 ± 0,3 vs. 6,4 ± 0,3 ml/min/g, p < 0,01) as compared with noninduced rats. Although c-AUCB treatment did not affect hypertension at 3 day (163 ± 4 mmHg), it significantly attenuated hypertension at day 11 (164 ± 2 mmHg). Moreover, c-AUCB restored RPF in both groups induced for 3 and 11 days (5,6 ± 0,5 and 5,4 ± 0,4 ml/min/g, respectively). Conclusions: These data demonstrate that sEH inhibitor exerts antihypertensive and renal vasodilator actions after the development of inducible malignant hypertension in Cyp1a1-Ren-2 transgenic rats.

Renal plasma flow and glomerular filtration rate duringacute kidney injury in man

During acute kidney injury (AKI), lowered glomerular filtration rate (GFR) is believed to be consequent to reduced renal plasma flow (RPF). We aimed to systematically evaluate the evidence for such an association. Using specific search terms, we systematically interrogated the Pub Med electronic reference database for studies of human AKI where renal plasma or blood flow and GFR were measured; older articles were then identified by screening bibliographies of retrieved reports. We identified 22 articles describing 250 patients (203 native kidney, 47 in renal allograft). Of these studies, 8 articles (110 patients) estimated effective renal plasma flow (ERPF) by clearance techniques and 14 articles (140 patients) estimated true renal plasma flow (TRPF). Mean RPF was 272 mL/min (95% CI 213–331) and GFR 13.9 mL/min (9.9–17.9). Mean TRPF was significantly greater than mean ERPF (344 vs. 180, p = 0.004) despite lower mean GFR (8.8 vs. 20.4, p = 0.002). There was no significant association between RPF and GFR between studies. Eleven studies presented individual patient data (76 patients: 49 TRPF, 27 ERPF); here, individual patient ERPF was associated with GFR (r2 = 0.52), but TRPF was not. During AKI in man, there is only a limited association between ERPF and GFR, and no detectable association between TRPF and GFR.

Effect of orchiectomy on renal function in control and diabetic rats with chronic inhibition of nitric oxide

1. Male gender is associated with higher blood pressure (BP) and more rapid loss of renal function in a spectrum of clinical and experimental renal diseases, including diabetic nephropathy. Consequently, modulation of testosterone levels could exert beneficial effects in the diabetic kidney. 2. The aim of the present study was to determine whether testosterone deficiency (orchiectomy) could influence BP and renal function in streptozotocin-diabetic rats, with or without accelerated endothelial dysfunction achieved by chronic inhibition of nitric oxide (NO) synthesis using N(G)-nitro-L-arginine methyl ester (l-NAME; 40-100 mg/L in the drinking water for 2 weeks), as well as in age-matched non-diabetic rats subjected to the same interventions. 3. Orchiectomy did not affect L-NAME-induced increases in BP in non-diabetic or diabetic rats. In non-diabetic rats, orchiectomy prevented L-NAME-induced increases in proteinuria. These effects on proteinuria were not observed in diabetic rats. In non-diabetic rats, orchiectomy had no effect on renal haemodynamics in animals receiving vehicle and did not affect L-NAME-induced changes in renal haemodynamics, characterized by reductions in renal plasma flow (RPF) and higher filtration fractions (FF). In intact diabetic rats, L-NAME treatment resulted in lower RPF. This difference was not observed in diabetic rats subjected to orchiectomy, although L-NAME-treated diabetic orchiectomized rats had lower RPF and higher FF compared with vehicle-treated intact diabetic rats. 4. In conclusion, we report modest beneficial effects of orchiectomy on proteinuria in normal, but not in diabetic, rats with inhibition of NO production. This suggests that testosterone reduction does not attenuate the deleterious impact of the diabetic metabolic milieu in the kidney.

In vivo renal arginine release is impaired throughout development of chronic kidney disease

The kidney is a major site of arginine synthesis where citrulline is converted to arginine via argininosuccinate synthase (ASS) and lyase (ASL). The rate-limiting step in arginine synthesis by the normal kidney is the rate of citrulline delivery and uptake to the renal cortex. We tested whether with chronic kidney disease (CKD) renal arginine synthesis may be compromised. Using the 5/6 renal ablation/infarction (A/I) injury model, we measured renal citrulline delivery and uptake as well as arginine release at early, moderate, and severe stages of CKD vs. healthy controls. The renal plasma flow (RPF) and arterial-renal venous difference was measured at baseline and during citrulline infusion. Citrulline delivery was reduced at all stages of disease due to marked reductions in RPF and despite moderately increased plasma citrulline. Early after 5/6 A/I, the kidney demonstrated a compensatory increase in citrulline uptake while at moderate and severe injury baseline citrulline uptake fell. At all stages of CKD, renal arginine release was markedly reduced. Citrulline infusion increased plasma citrulline in all groups, resulting in increased renal delivery vs. baseline. In healthy kidneys and early injury, citrulline uptake increased with the infusion, but only in the normal kidney did arginine production increase in parallel with the increased citrulline uptake. At moderate and severe injury, there was no increase in citrulline uptake or arginine production. The fall in arginine production in 5/6 A/I was due to an early loss of ASS and ASL conversion of citrulline, which combined with a later reduction in citrulline uptake.

Exogenous Citrulline (Cit) on Renal Uptake in Various Stages of 5/6 Ablation/Infarction (A/I) Chronic Kidney Disease (CKD)

The kidney is a major site of L‐Arginine (arg) synthesis, and with renal disease arg synthesis may be compromised. The first and rate‐limiting step in renal arg synthesis is the rate of cit delivery to the renal cortex. Using the 5/6 renal ablation/infarction (A/I) injury model, we measured renal cit delivery and extraction at 2 stages of disease progression (4‐5 wk; n=7 and 10‐12 wk; n=6) after A/I vs. sham (n=7). The arterial‐renal venous difference was measured at baseline and during cit infusion. Both stages of injury resulted in decreased baseline cit delivery to the kidney due to marked reductions in renal plasma flow (RPF) and despite increased plasma cit. The % cit extraction at baseline was unaffected by CKD, hence cit uptake fell markedly with injury. Cit infusion increased RPF only in healthy rats (possibly through increased NO production). Plasma cit increased in all groups resulting in increased renal cit delivery vs baseline. In healthy kidneys cit extraction and uptake increased. However, despite increased delivery neither renal cit extraction nor uptake was increased at either stage of injury. The inability of the injured kidney to take up cit indicates a marked reduction and saturation of the renal cit transport capacity.*p&lt;0.05, *p&lt;0.01, ***p&lt;0.001 vs. Sham, +p&lt;0.05, ++p&lt;0.01, +++p&lt;0.001 vs. baseline within group.

Modeling Preeclampsia: The True Model for the Uniquely Human Disease Preeclampsia Is the Human Female Not the Pregnant Rat

To the Editor: Gadonski et al1 describe a series of elegant experiments in which they used a rodent (rat) model to show that chronic reduction in uterine perfusion pressure was associated with an elevation of arterial pressure and that this elevation in AP was associated with a rise in serum levels of interleukin-6. They further showed that this rise in arterial pressure occurs after chronic elevation of interleukin-6 in pregnant but not in nonpregnant rats and is associated with increase in renal vascular resistance and reduction in renal plasma flow, as well as glomerular filtration …

Rolle des L-Arginin/NO-Stoffwechselweges im akuten Nierenversagen

Role of the L-arginine/NO-pathway in acute renal failure ■ Summary Regulation of renal hemodynamics – in particular intraglomerluar hemodynamics -is closely related to the L-arginine/ NO-pathway. Almost all forms of acute renal failure (ARF) are characterized by a reduction in renal plasma flow (RPF) and increased renal vascular resistance. NO, metabolized from L-arginine, is capable of improving renal function due to its vasorelaxing properties in almost all models of ARF, whereas unselective inhibition of nitric oxide synthase (NOS) generally exerts contrary effects. Increased tubular generation of oxygen radicals in the early course of ischemic ARF indicates increased oxidative stress. Simultaneously regulatory changes in expression of iNOS (inducible NOS) and eNOS (endothelial NOS) are observed. Apart from the positive functional effects with L-arginine supplementation a remarkable reduction in the formation of oxygen radicals and reduced overexpression of iNOS are observed. This is important, because in ischemic ARF increased expression of iNOS is accompanied by increased formation of oxygen radicals and peroxynitrite. Both substances are highly reactive and exert many cytotoxic effects. eNOS-derived NO probably plays such an important role in maintaining and improving renal and intraglomerular hemodynamics that negative effects from iNOS-derived NO are overcome. The roles of NOS are different for different types of NOS and also depend on the time course of ARF. Future management strategies should focus on the interplay between antioxidants and NO regulators and the correlation of reactive oxygen species and NO.