The molecular mechanism of CD81 antibody inhibition of metastasis.

Metastases are reduced in CD81KO mice. In addition, a unique anti-CD81 antibody, 5A6, inhibits metastasis in vivo and invasion and migration in vitro. Here, we probed the structural components of CD81 required for the antimetastatic activity induced by 5A6. We found that the removal of either cholesterol or the intracellular domains of CD81 did not affect inhibition by the antibody. We show that the uniqueness of 5A6 is due not to increased affinity but rather to its recognition of a specific epitope on the large extracellular loop of CD81. Finally, we present a number of CD81 membrane-associated partners that may play a role in mediating the 5A6 antimetastatic attributes, including integrins and transferrin receptors.

Combination of hyperglycaemia and hyperlipidaemia induces endothelial dysfunction: Role of the endothelin and nitric oxide systems.

Endothelial dysfunction (ED) is a key feature of diabetes and is a major cause of diabetic vasculopathy. Diabetic patients who also exhibit hyperlipidaemia suffer from accelerated vascular complications. While the deleterious effects of high glucose levels (HG) and hyperlipidaemia alone on ED are well established, the effects of combined hyperlipidaemia and HG have not been thoroughly studied. Therefore, the current study examines whether HG and hyperlipidaemia exert synergistic ED, and explores the mechanisms underlying this phenomenon. We applied multi-disciplinary approaches including cultured HUVECs and HMEC-1 as well as knockout mice CByJ.129S7(B6)-Ldlrtm1Her/J (LDLR-/- ) to investigate the mechanisms underlying combined HG and hyperlipidaemia-induced ED. Incremental doses of glucose in the presence or absence of OxLDL were added to HUVECs and HMEC-1. After 5 days, the status of nitric oxide (NO) and endothelin (ET)-1 systems as well as their signal transduction were assessed using Western blot, ELISA and immunoreactive staining. The effects of chronic combination of HG and hyperlipidaemia on endothelial integrity and function as well as alterations in circulatory NO and ET-1 systems were examined in knockout mice LDLR-/- and their wild-type. HUVEC cells exposed to HG and OxLDL displayed enhanced ET-1 production, more than HG or OxLDL when added alone. Overproduction of ET-1 stems from up-regulation of endothelin converting enzyme (ECE)-1 as observed under these conditions. In contrast, combination of HG and OxLDL dramatically decreased both total endothelial NO synthase (eNOS) by 60%, and activated eNOS (peNOS) by 80%. Moreover, NRF2 decreased by 42% and its active form (pNRF2) by 56%, as compared to baseline. Likewise, ETB levels decreased by 64% from baseline on endothelial cells. Furthermore, diabetic LDLR-/- mice displayed a higher blood pressure, plasma triglycerides, cholesterol, ET-1 and NO2/NO3 levels, when compared with normoglycemic LDLR-/- and BALB mice. Combined hyperglycaemia and hyperlipidaemia activates the ET system and attenuates the nitric oxide system with the Nrf2 signalling pathway. These findings suggest that perturbations in these paracrine systems may contribute to ED.

Increased Intra-abdominal Pressure Induces Acute Kidney Injury in an Experimental Model of Congestive Heart Failure.

BACKGROUND: Congestive heart failure (CHF) entails a complex interaction between the heart and the kidney that represents a clinical entity called cardiorenal syndrome (CRS). One of the mechanisms underlying CRS includes increased intra-abdominal pressure (IAP). We examined the effect of elevated IAP on kidney function in rats with low- and high-output CHF. METHODS AND RESULTS: Rats with compensated and decompensated CHF induced by means of aortocaval fistula, rats with myocardial infraction (MI) induced by means of left anterior descending artery ligation, and sham control rats were subjected to either 10 or 14 mm Hg IAP. Urine flow (V), Na+ excretion (UNaV), glomerular filtration rate (GFR), and renal plasma flow (RPF) were determined. The effects of pretreatment with tadalafil (10 mg/kg orally for 4 days) on the adverse renal effects of IAP were examined in decompensated CHF and MI. Basal V and GFR were significantly lower in rats with decompensated CHF compared with sham control rats. Decompensated CHF rats and MI rats subjected to 10 and 14 mm Hg IAP exhibited more significant declines in V, UNaV, GFR and RPF than compensated and sham controls. Elevated IAP also induced tubular injury, as evidenced by significantly increased absolute urinary excretion of neutrophil gelatinase-associated lipocalin. In addition, in a nonquantitative histologic analysis, elevated IAP was associated with increase in necrosis and cell shedding to the tubule lumens, especially in the decompensated CHF subgroup. Pretreatment of decompensated CHF rats and MI rats with tadalafil ameliorated the adverse renal effects of high IAP. CONCLUSIONS: Elevated IAP contributes to kidney dysfunction in high- and low-cardiac output CHF. IAP induces both hemodynamic alterations and renal tubular dysfunction. These deleterious effects are potentially reversible and can be ameliorated with the use of phosphodiesterase-5 inhibition.

Dataset on mice body weights and food intake following treatment with PG545.

This data article contains analysis of data observed in E0 mice placed on high fat diet, and treated by intraperitoneal injections of either normal saline (control) or the heparanase inhibitor PG545, in two different doses. Mice body weights and food intake were measured weekly and analyzed data are presented in graphs. Data will be of value for further understanding the role of the enzyme heparanase in controlling food intake and body weight. For further interpretations, see please "Heparanase inhibition attenuates atherosclerosis progression and liver steatosis in E0 mice" (Muhammad et al. 2018).

Heparanase inhibition attenuates atherosclerosis progression and liver steatosis in E0 mice.

BACKGROUND AND AIMS: Increased oxidative stress is associated with accelerated atherosclerosis. Emerging evidence highlights the role of heparanase in atherogenesis, where heparanase inhibitor PG545 reduces oxidative stress in apolipoprotein E deficient mice (E0 mice). Herein, we studied the effects of PG545 on atherosclerosis progression in E0 mice. METHODS: Male E0 mice fed a high-fat diet (n = 20) were divided into 3 groups treated with weekly intraperitoneal injections of either low (0.2 mg/mouse) or high dose (0.4 mg/mouse)PG545 or normal saline (controls) for twelve weeks. Body weight and food intake were measured weekly. At the end of the treatment period, blood pressure was measured, animals were sacrificed and serum samples were collected and assessed for biochemical parameters and oxidative stress. Aortic vessels and livers were collected for atherosclerotic plaques and histopathological analysis, respectively. RESULTS: Blood pressure decreased in mice treated with low, but not high dose of PG545. In addition, heparanase inhibition caused a dose-dependent reduction in serum oxidative stress, total cholesterol, low-density lipoproteins, triglycerides, high-density lipoproteins, and aryl esterase activity. Although food intake was not reduced by PG545, body weight gain was significantly attenuated in PG545 treated groups. Both doses of PG545 caused a marked reduction in aortic wall thickness and atherosclerosis development, and liver steatosis. Liver enzymes and serum creatinine were not affected by PG545. CONCLUSIONS: Heparanase inhibition by PG545 caused a significant reduction in lipid profile and serum oxidative stress along with attenuation of atherosclerosis, aortic wall thickness, and liver steatosis. Moreover, PG545 attenuated weight gain without reducing food intake. Collectively, these findings suggest that heparanase blockade is highly effective in slowing atherosclerosis formation and progression, and decreasing liver steatosis.

Leucine supplementation attenuates macrophage foam-cell formation: Studies in humans, mice, and cultured macrophages.

Whereas atherogenicity of dietary lipids has been largely studied, relatively little is known about the possible contribution of dietary amino acids to macrophage foam-cell formation, a hallmark of early atherogenesis. Recently, we showed that leucine has antiatherogenic properties in the macrophage model system. In this study, an in-depth investigation of the role of leucine in macrophage lipid metabolism was conducted by supplementing humans, mice, or cultured macrophages with leucine. Macrophage incubation with serum obtained from healthy adults supplemented with leucine (5 g/d, 3 weeks) significantly decreased cellular cholesterol mass by inhibiting the rate of cholesterol biosynthesis and increasing cholesterol efflux from macrophages. Similarly, leucine supplementation to C57BL/6 mice (8 weeks) resulted in decreased cholesterol content in their harvested peritoneal macrophages (MPM) in relation with reduced cholesterol biosynthesis rate. Studies in J774A.1 murine macrophages revealed that leucine dose-dependently decreased cellular cholesterol and triglyceride mass. Macrophages treated with leucine (0.2 mM) showed attenuated uptake of very low-density lipoproteins and triglyceride biosynthesis rate, with a concurrent down-regulation of diacylglycerol acyltransferase-1, a key enzyme catalyzing triglyceride biosynthesis in macrophages. Similar effects were observed when macrophages were treated with α-ketoisocaproate, a key leucine metabolite. Finally, both in vivo and in vitro leucine supplementation significantly improved macrophage mitochondrial respiration and ATP production. The above studies, conducted in human, mice, and cultured macrophages, highlight a protective role for leucine attenuating macrophage foam-cell formation by mechanisms related to the metabolism of cholesterol, triglycerides, and energy production. © 2018 BioFactors, 44(3):245-262, 2018.

The role of high density lipoprotein in Type 1 Gaucher disease.

Type I Gaucher Disease (GD1) is known to be associated with hypocholesterolemia and reduced levels of low density lipoprotein (LDL) and high density lipoprotein (HDL). In this study we aimed to correlate disease severity with HDL levels and to evaluate the effect of enzyme replacement therapy (ERT) on HDL levels as well as estimating the frequency of cardiovascular events in GD. Two groups of GD1 patients were evaluated: 30 untreated and 36 patients on ERT. Disease severity, biomarkers of GD and lipid levels were evaluated in the two groups. The Zimran Severity Score Index (SSI) was used to estimate disease severity and the effect of ERT on HDL levels was evaluated, as well as the frequency of cardiovascular disease. GD1 patients with more severe disease (SSI median 11) had significantly lower levels of HDL (median 23mg/dL), compared to patients with milder (SSI median 4.5) disease (median 37mg/dL p=0.001). HDL levels increased after ERT. Despite lower HDL levels in patients with more severe disease, a low frequency of cardiovascular events was detected. HDL level should be used in GD as a biomarker for diagnosis, monitoring and estimation of ERT effect.

Heparanase Inhibition Reduces Glucose Levels, Blood Pressure, and Oxidative Stress in Apolipoprotein E Knockout Mice.

BACKGROUND: Atherosclerosis is a multifactorial process. Emerging evidence highlights a role of the enzyme heparanase in various disease states, including atherosclerosis formation and progression. OBJECTIVE: The aim of the study was to investigate the effect of heparanase inhibition on blood pressure, blood glucose levels, and oxidative stress in apoE-/- mice. METHODS: Male apoE-/- mice were divided into two groups: one treated by the heparanase inhibitor PG545, administered intraperitoneally weekly for seven weeks, and the other serving as control group (injected with saline). Blood pressure was measured a day before sacrificing the animals. Serum glucose levels and lipid profile were measured. Assessment of oxidative stress was performed as well. RESULTS: PG545 significantly lowered blood pressure and serum glucose levels in treated mice. It also caused significant reduction of the serum oxidative stress. For safety concerns, liver enzymes were assessed, and PG545 caused significant elevation only of alanine aminotransferase, but not of the other hepatic enzymes. CONCLUSION: Heparanase inhibition by PG545 caused marked reduction of blood pressure, serum glucose levels, and oxidative stress in apolipoprotein E deficient mice, possibly via direct favorable metabolic and hemodynamic changes caused by the inhibitor. Possible hepatotoxic and weight wasting effects are subject for future investigation.

Atherogenicity of amino acids in the lipid-laden macrophage model system in vitro and in atherosclerotic mice: a key role for triglyceride metabolism.

Atherosclerosis-related research has focused mainly on the effects of lipids on macrophage foam cell formation and atherogenesis, whereas the role of amino acids (AAs) was understudied. The current study aimed to identify anti- or pro-atherogenic AA in the macrophage model system and to elucidate the underlying metabolic and molecular mechanisms. J774A.1 cultured macrophages were treated with increasing concentrations of each 1 of the 20 AAs. Macrophage atherogenicity was assessed in terms of cellular toxicity, generation of reactive oxygen species (ROS) and cellular cholesterol or triglyceride content. At nontoxic concentrations (up to 1 mM), modest effects on ROS generation or cholesterol content were noted, but six specific AAs significantly affected macrophage triglyceride content. Glycine, cysteine, alanine and leucine significantly decreased macrophage triglyceride content (by 24%-38%), through attenuated uptake of triglyceride-rich very low-density lipoprotein (VLDL) by macrophages. In contrast, glutamate and glutamine caused a marked triglyceride accumulation in macrophages (by 107% and 129%, respectively), via a diacylglycerol acyltransferase-1 (DGAT1)-dependent increase in triglyceride biosynthesis rate with a concurrent maturation of the sterol regulatory element-binding protein-1 (SREBP1). Supplementation of apolipoprotein E-deficient (apoE-/-) mice with glycine for 40 days significantly decreased the triglyceride levels in serum and in peritoneal macrophages (MPMs) isolated from the mice (by 19%). In contrast, glutamine supplementation significantly increased MPM ROS generation and the accumulation of cholesterol and that of triglycerides (by 48%), via enhanced uptake of LDL and VLDL. Altogether, the present findings reveal some novel roles for specific AA in macrophage atherogenicity, mainly through modulation of cellular triglyceride metabolism.

Aqueous or lipid components of atherosclerotic lesion increase macrophage oxidation and lipid accumulation.

INTRODUCTION AND OBJECTIVE: Understanding the interactions among atherosclerotic plaque components and arterial macrophages, is essential for elucidating the mechanisms involved in the development of atherosclerosis. We assessed the effects of lesion extracts on macrophages. METHODS: Mouse peritoneal macrophages from atherosclerotic normoglycemic or hyperglycemic apoE(-/-) mice were incubated with aortic aqueous or with aortic lipidic extracts (mAAE or mALE) derived from these mice. In parallel, J774A.1 cultured macrophages were incubated with increasing concentrations of extracts prepared from human carotid lesions: polar lesion aqueous extract (hLAE), nonpolar lesion lipid extract (hLLE), or with their combination. In all the above systems we performed analyses of macrophage oxidative status, cholesterol, and triglyceride metabolism. RESULTS: Aqueous or lipid extracts from either mice aorta or from human carotid lesions significantly increased macrophage oxidative stress as determined by reactive oxygen species (ROS) analysis. In parallel, a compensatory increase in the cellular antioxidant paraoxonase2 (PON2) activity and in macrophage glutathione content were observed following incubation with all extracts. Macrophage triglyceride mass and triglyceride biosynthesis rate were both significantly increased following treatment with the lipid extracts, secondary to upregulation of DGAT1. All extracts decreased cholesterol biosynthesis rate, through downregulation of HMGCR, the rate limiting enzyme in cholesterol biosynthesis. The combination of the human lesion extracts had the most significant effects. CONCLUSION: The present study demonstrates that atherosclerotic plaque constituents enhance macrophage cellular oxidative stress, and accumulation of cholesterol and triglycerides, as shown in both in vivo and in vitro model systems.

The Role of Angiotensin II and Cyclic AMP in Alveolar Active Sodium Transport.

Active alveolar fluid clearance is important in keeping airspaces free of edema. Angiotensin II plays a role in the pathogenesis of hypertension, heart failure and others. However, little is known about its contribution to alveolar fluid clearance. Angiotensin II effects are mediated by two specific receptors; AT1 and AT2. The localization of these two receptors in the lung, specifically in alveolar epithelial cells type II, was recently reported. We hypothesize that Angiotensin II may have a role in the regulation of alveolar fluid clearance. We investigated the effect of Angiotensin II on alveolar fluid clearance in rats using the isolated perfused lung model and isolated rat alveolar epithelial cells. The rate of alveolar fluid clearance in control rats was 8.6% ± 0.1 clearance of the initial volume and decreased by 22.5%, 28.6%, 41.6%, 48.7% and 39% in rats treated with 10-10 M, 10-9 M, 10-8 M, 10-7 M or 10-6 M of Ang II respectively (P < 0.003). The inhibitory effect of Angiotensin II was restored in losartan, an AT1 specific antagonist, pretreated rats, indicating an AT1 mediated effect of Ang II on alveolar fluid clearance. The expression of Na,K-ATPase proteins and cAMP levels in alveolar epithelial cells were down-regulated following the administration of Angiotensin II; suggesting that cAMP may be involved in AngII-induced reduced Na,K-ATPase expression, though the contribution of additional factors could not be excluded. We herein suggest a novel mechanism of clinical relevance by which angiotensin adversely impairs the ability of the lungs to clear edema.

Cardiac and renal distribution of ACE and ACE-2 in rats with heart failure.

Congestive heart failure is often associated with impaired kidney function. Over-activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid salt and water retention in heart failure. While the expression of angiotensin converting enzyme (ACE), a key enzyme in the synthesis of angiotensin II (Ang II), is well established, the expression of angiotensin converting enzyme-2 (ACE-2), an enzyme responsible for angiotensin 1-7 generation, is largely unknown. This issue is of a special interest since angiotensin 1-7 counteracts many of the proliferative and hypertensive effects of angiotensin II. Therefore, the present study was designed to investigate the expression of both enzymes in the kidney and heart of rats with heart failure. Heart failure (CHF) was induced in male Sprague Dawley rats (n=9) by the creation of a surgical aorto-caval fistula. Sham-operated rats served as controls (n=8). Two weeks after surgery, the animals were sacrificed and their hearts and kidneys were harvested for assessment of cardiac remodeling and ACE and ACE-2 immunoreactivity by immunohistochemical staining. ACE immunostaining was significantly increased in the kidneys (4.34 ± 0.39% vs. 2.96 ± 0.40%, P<0.05) and hearts (4.57 ± 0.54% vs. 2.19 ± 0.37%, P<0.01) of CHF rats as compared with their sham controls. In a similar manner, ACE-2 immunoreactivity was also elevated in the kidneys (4.65 ± 1.17% vs. 1.75 ± 0.29%, P<0.05) and hearts (5.48 ± 1.11% vs. 1.13 ± 0.26%, P<0.01) of CHF rats as compared with their healthy controls. This study showed that both ACE and ACE-2 are overexpressed in the cardiac and renal tissues of animals with heart failure as compared with their sham controls. The increased expression of the beneficial ACE-2 in heart failure may serve as a compensatory response to the over-activity of the deleterious isoform, namely, angiotensin converting enzyme 1(ACE-1).

Sensor arrays based on nanoparticles for early detection of kidney injury by breath samples.

The outcomes of acute kidney injury (AKI) could be severe and even lethal, if not diagnosed in its early stages and treated appropriately. Blood and urine biomarkers, currently in use as indicators for kidney function, are either inaccurate in various cases or not timely. We report on dramatic changes in exhaled breath composition, associated with kidney dysfunction after ischemic insult in rat models. Gas chromatography linked mass spectrometry examination of breath samples indicated significant elevations in the concentration of three exhaled volatile organic compounds, two to six hours after AKI was surgically induced. Relying on these findings, we introduce an array of sensors, based on organic-layer capped gold nanoparticles, sensitive to odor changes. The ability of the array to detect AKI via breath testing was examined and scored a sensitivity of 96%, only one hour after disease induction. FROM THE CLINICAL EDITOR: In this study, organic-layer capped gold nanoparticle-based biosensors are used to analyse breath samples in an acute kidney injury model, capitalizing on the observation that specific volatile organic compounds are present in breath samples in that condition. The authors report excellent sensitivity in as little as one hour after acute kidney injury. This method, if commercialized, may replace the current blood and urine sample analysis-based tests with a more convenient, rapid and accurate nanotechnology-based method.

Nephroprotective effects of TVP1022, a non-MAO inhibitor S-isomer of rasagiline, in an experimental model of diabetic renal ischemic injury.

Ischemic acute kidney injury (iAKI) in diabetes mellitus is associated with a rapid deterioration of kidney function, more than in nondiabetic subjects. TVP1022, a non-MAO inhibitor S-isomer of rasagiline, possesses antioxidative and antiapoptotic activities. The current study examines the effects of TVP1022 and tempol on iAKI in diabetic rats. Diabetes was induced by streptozotocin. iAKI was induced by clamping the left renal artery for 30 min in both diabetic and nondiabetic rats. The right intact kidney served as a control. Forty-eight hours following ischemia, urinary flow (V), sodium excretion (UNaV), and glomerular filtration rate (GFR) in both ischemic and nonischemic kidneys were determined. The nephroprotective effects of tempol and TVP1022 were examined in these rats. Hematoxylin and eosin staining, 4-hydroxynonenal (4-HNE) immunofluorescence, and nitrotyrosine immunohistochemistry were performed on renal tissues of the various experimental groups. Compared with normoglycemic rats, iAKI in diabetic animals caused more profound reductions in V, UNaV, and GFR. Tempol and TVP1022 treatment increased GFR two- and four-fold in diabetic ischemic kidney, respectively. Besides hemodynamic perturbations, iAKI markedly increased renal immunoreactive 4-HNE and nitrotyrosine staining in both diabetic and nondiabetic rats. Moreover, iAKI increased medullary necrosis, congestion, and casts. Noteworthy, these increases were to a larger extent in ischemic diabetic kidneys. TVP1022, and to a lesser extent tempol, decreased nitrotyrosine and 4-HNE immunoreactivities and necrosis and cast formation in the renal medulla. TVP1022 treatment improves renal dysfunction and histological changes in an iAKI diabetic model and suggests a role for TVP1022 therapy in kidney injury.

Acute obstructive jaundice and chronic cirrhosis protect against the adverse renal effects of pneumoperitoneum: role of nitric oxide.

BACKGROUND: Obstructive jaundice and cirrhosis are associated with impaired renal function. Previously we demonstrated that increased intra-abdominal pressure (IAP, pneumoperitoneum) in normal rats induced renal dysfunction. This study investigated the renal effects of pneumoperitoneum in rats with acute jaundice and cirrhotic rats. METHODS: Following a baseline period, rats with obstructive jaundice or cirrhosis induced by acute or chronic bile duct ligation (BDL), respectively, and their sham-controls were subjected to consecutive IAPs of 10 and 14 mmHg for 45 min each. Urine flow (V), Na(+) excretion (UNaV), glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary NO metabolites ([Formula: see text]) and cGMP (UcGMP) were determined. RESULTS: Elevating IAP from 0 to 10 and 14 mmHg in normal rats caused IAP-dependent reductions in V, UNaV, GFR, RPF, [Formula: see text] and UcGMP. Basal renal function and hemodynamics were lower in rats with obstructive jaundice. In contrast to normal rats, application of elevated IAP of 10 and 14 mmHg significantly improved V, UNaV, GFR, RPF, and MAP along with increased [Formula: see text] and preserved UcGMP. Similarly, when identical IAP conditions were applied to cirrhotic rats, no deleterious changes in V, UNaV, GFR or RPF were observed. CONCLUSIONS: Application of pneumoperitoneum to rats with acute BDL improves kidney function and renal hemodynamics. Likewise, increased IAP does not exert adverse renal effects in cirrhotic rats. These effects are distinct from the deleterious renal consequences of increased IAP in normal rats. Perturbations in the generation of NO/cGMP during IAP in normal rats but not in rats with BDL or cirrhosis may contribute to these differences.

Phosphodiesterase 5 inhibition protects against increased intra-abdominal pressure-induced renal dysfunction in experimental congestive heart failure.

AIMS: Congestive heart failure (CHF) is associated with impaired renal function. Previously, we have demonstrated that rats with decompensated CHF exhibited exaggerated sensitivity to the adverse renal effects of increased increased intra-abdominal pressure (IAP) as compared with normal controls. This study tested whether phosphodiesterase 5 (PDE5) inhibition protects against the adverse renal effects of increased IAP in rats with CHF. METHODS AND RESULTS: Following baseline periods, rats with compensated and decompensated CHF induced by the placement of an aorto-caval fistula (ACF), rats with myocardial infarction (MI) induced by left anterior descending (LAD) artery ligation, and sham controls were subjected to consecutive IAPs: 7, 10, or 14 mmHg. Urine flow (V), Na(+) excretion (U(Na)V), glomerular filtration rate (GFR), and renal plasma flow (RPF) were determined. The effects of pre-treatment with tadalafil on the adverse renal effects of IAP were examined in rats with decompensated CHF and MI. Elevation of IAP to 10 and 14 mmHg produced linear reductions in these parameters. Basal renal function and haemodynamics were lower in CHF rats. Decompensated CHF rats and MI rats that were subjected to 10 and 14 mmHg exhibited exaggerated declines in V, U(Na)V, GFR, and RPF. In contrast, no adverse renal effects were observed in rats with compensated CHF subjected to IAP. Pre-treatment of decompensated CHF rats and MI rats with tadalafil ameliorated the adverse renal effects of high IAP. CONCLUSION: Decompensated CHF and MI rats are vulnerable to the adverse renal effects of IAP. Tadalafil abolishes IAP-induced renal dysfunction, supporting a therapeutic role for PDE5 inhibition in CHF associated with ascites.

Involvement of the endothelin and nitric oxide systems in the pathogenesis of renal ischemic damage in an experimental diabetic model.

AIMS: Ischemic acute kidney injury (iAKI) in experimental diabetes mellitus (DM) is associated with a rapid kidney dysfunction more than in non-diabetic rats. We hypothesize that this vulnerability is due to excessive endothelin-1 (ET-1) expression along with dysregulation of nitric oxide synthase (NOS) isoforms. The aim of the present study was to assess the impact of ischemia on renal function in diabetic rats as compared with non-diabetic rats, and to investigate the involvement of ET-1 and NO systems in the susceptibility of diabetic kidney to ischemic damage. MAIN METHODS: DM was induced by Streptozotocin. iAKI was induced by clamping of left renal artery for 30 min. Right intact kidney served as control. 48 h following ischemia, clearance protocols were applied to assess glomerular filtration rate (GFR), urinary flow (V) and sodium excretion (U(Na)V) in both kidneys. The renal effects of ABT-627, ET(A) antagonist; A192621.1, ET(B) antagonist; L-NAME, NOS non-selective inhibitor; 1400 W, inducible NOS (iNOS) inhibitor; and NPLA, neuronal NOS (nNOS) inhibitor, were assessed following ischemic renal injury in diabetic rats. KEY FINDINGS: Induction of iAKI in diabetic and non-diabetic rats caused significant reductions in GFR, V, and U(Na)V, which were greater in diabetic than non-diabetic rats. While, treatment with ABT-627 decreased V and U(Na)V, and increased GFR, A192621.1 decreased all these parameters. L-NAME, 1400 W, and NPLA improved GFR in the ischemic diabetic kidney. SIGNIFICANCE: Excessive vasoconstrictive effects of ET-1 via ET(A) and upregulation of iNOS, are partly responsible for the impaired recovery of renal function following ischemia in diabetic rats.

Pneumoperitoneum aggravates renal function in cases of decompensated but not compensated experimental congestive heart failure: role of nitric oxide.

PURPOSE: Congestive heart failure is associated with impaired renal function. Previously we noted that increased intra-abdominal pressure (pneumoperitoneum) in normal rats induced renal dysfunction. In this study we investigated the renal effects of pneumoperitoneum in rats with compensated (urinary Na(+) excretion greater than 1,200 µEq per 24 hours) and decompensated (urinary Na(+) excretion less than 200 µEq per 24 hours) congestive heart failure, and the possible involvement of nitric oxide in these effects. MATERIALS AND METHODS: After a baseline period rats with congestive heart failure induced by aorto-caval fistula and sham operated controls underwent consecutive intra-abdominal pressures of 7, 10 or 14 mm Hg for 45 minutes each. Urinary flow, urinary Na(+) excretion, glomerular filtration rate, renal plasma flow and urinary nitric oxide metabolites were determined. RESULTS: There were no changes in urinary flow, urinary Na(+) excretion, glomerular filtration rate or renal plasma flow during 7 mm Hg insufflation in controls. However, significant decreases in these parameters were observed during 10 and 14 mm Hg in correlation with intra-abdominal pressure. Baseline renal function and hemodynamics were lower in rats with congestive heart failure in correlation with disease severity. Rats with decompensated congestive heart failure that underwent 10 and 14 mm Hg showed aggravated decreases in urinary flow, urinary Na(+) excretion, glomerular filtration rate and renal plasma flow. In contrast, no adverse renal effects were observed in rats with compensated congestive heart failure under identical intra-abdominal pressure conditions. Despite unaltered baseline urinary nitric oxide metabolites in the 2 congestive heart failure subgroups, the decompensated group showed decreased urinary nitric oxide metabolites after 14 mm Hg. Finally, rats with compensated congestive heart failure pretreated with the nitric oxide synthase inhibitor L-NAME showed worse renal function in response to pneumoperitoneum. CONCLUSIONS: Decompensated congestive heart failure renders rats susceptible to the adverse renal effects of pneumoperitoneum, a phenomenon that may involve alterations in the renal nitric oxide system.

Peroxisome proliferator-activated receptor alpha and alpha/gamma agonists do not cause impairment in renal function in the rat.

BACKGROUND/AIMS: Patients treated with peroxisome proliferator-activated receptor analogs (PPAR) alpha or alpha/gamma may develop a transient and reversible increase in serum creatinine, the mechanism of which remains obscure. This study evaluates whether treatment with either PPAR-alpha or -alpha/gamma analogs, fenofibrate or tesaglitazar, may cause deterioration in renal hemodynamics or exert direct tubular or glomerular nephrotoxic effects in rats. METHODS: Male Sprague-Dawley rats (300-320 g) were treated per os with fenofibrate (300 mg/kg/day), tesaglitazar (1.2 mg/kg/day) or vehicle, for 14 days. Glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by inulin clearance and ultrasonic flowmetry, and cumulative excretion of sodium and creatinine were assessed. Biomarkers of glomerular and tubular injury were measured, including urinary albumin excretion and renal mRNA levels of kidney injury molecule 1 (Kim-1), lipocalin 2 (Lcn2), and osteopontin (Spp1). RESULTS: Fenofibrate and tesaglitazar improved the lipid profile, but caused no detectable decrease in GFR or RBF compared with vehicle-treated rats. Furthermore, the cumulative excretions of sodium and creatinine were not altered by the drugs. Finally, there was no significant difference between drug- and vehicle-treated groups in urinary albumin excretion or in the expression of renal injury biomarkers. CONCLUSIONS: In the rat, no direct nephrotoxic effect or deterioration in renal hemodynamics and function were observed following treatment with fenofibrate or tesaglitazar.