Catheter-Based Radiofrequency Renal Denervation: Location Effects on Renal Norepinephrine.

BACKGROUND: Clinical studies indicate that blood pressure (BP)-lowering effects of radiofrequency (RF) renal denervation (RD) are sustained for up to 2 years, although a recent clinical trial failed to find a major effect compared to sham treatment. In most previous studies, the efficacy of RD has not been assessed. The current study determined whether RD in different regions of the renal artery causes different degrees of RD as assessed with renal norepinephrine (NE) levels. METHODS AND RESULTS: Unilateral RD was performed on 14 pigs divided into 3 groups: RD near the ostium, in the main renal artery near the bifurcation, and in extrarenal branches of the renal artery. After 2 weeks post-RD, the pigs were euthanized, renal cortex tissue was collected for NE measurement, and renal arteries were prepared for histological analysis. Renal NE decreased by 12% with RD at the ostium, 45% with RD near the bifurcation in the main renal artery, and 74% when RD was performed in extrarenal artery branches. The number of renal nerves was greatest in extrarenal branches and in the main artery compared to the ostium and the average distance from the lumen was greatest for nerves at the ostium and least at the branches. CONCLUSIONS: RF RD lowers renal NE more significantly when performed in branches of the renal artery closer to the kidney. Increased efficacy of RF RD in extrarenal arterial branches may be due to the greater number of nerves in close proximity to the artery lumen in the branches.

Renal denervation therapy for hypertension: pathways for moving development forward.

This scientific statement provides a summary of presentations and discussions at a cardiovascular Think Tank co-sponsored by the American Society of Hypertension (ASH), the United States Food and Drug Administration (FDA), and the National Heart, Lung, and Blood Institute (NHLBI) held in North Bethesda, Maryland, on June 26, 2014. Studies of device therapies for the treatment of hypertension are requested by regulators to evaluate their safety and efficacy during their development programs. Think Tank participants thought that important considerations in undertaking such studies were: (1) Preclinical assessment: how likely it is that both efficacy and safety data indicating benefit in humans will be obtained, and/or whether a plausible mechanism of action for efficacy can be identified; (2) Early human trial(s): the ability to determine that the device has an acceptable benefit-to-risk balance for its use in the intended patient population and without the influence of drug therapy during a short-term follow-up period; and (3) Pivotal Phase III trial(s): the ability to prove the effectiveness of the device in a broad population in which the trial can be made as non-confounded as possible while still allowing for the determination for benefits when added to antihypertensive therapies.

Is the peritoneum a significant transport barrier in peritoneal dialysis?

OBJECTIVES: The anatomic peritoneum is often considered equivalent to the barrier between the dialysate and the blood, and is also called "the peritoneal membrane." Our hypothesis is that the normal peritoneum is not a significant barrier to solute or water flow. The goal of this study was to explore the effects of alteration of the anatomic peritoneum on the transperitoneal transport of water and solute. DESIGN: In vivo transport experiments were carried out in control and treated rats. Treatments consisted of frequent mixing of the peritoneal solution versus no mixing, drying the peritoneum prior to the experiment, or selective removal of the entire peritoneum. Transport experiments were carried out via a plastic chamber affixed to the parietal peritoneum. After measuring solute transport or osmotically induced filtration, the tissue underlying the chamber was collected and stained for histology. RESULTS: Mixing the chamber solution every 5 minutes versus no mixing over 90 minutes did not result in a significant change in the mass transfer coefficient for mannitol (MTCmannitol, n = 14, p > 0.25). Drying the peritoneum prior to the transport experiment did not significantly alter the MTC of albumin or mannitol (n = 17, p > 0.6; n = 19, p > 0.1, respectively). Manual drying did not remove or significantly alter the apparent peritoneal coating on the surface of the mesothelium. Removal of the entire peritoneum did not significantly alter the osmotically induced volume flux from the tissue, nor did it change the MTCmannitol (n = 9, p > 0.9; n = 9, p > 0.4, respectively). CONCLUSIONS: Mixing of the solution directly over the tissue, manual drying of the peritoneum, or removal of the entire peritoneum does not result in significant alterations in transport. We conclude that the anatomic peritoneum is relatively unimportant as a physical transport barrier in peritoneal dialysis.

Catheter-based radiorefrequency renal denervation lowers blood pressure in obese hypertensive dogs.

BACKGROUND: Obesity-induced hypertension appears to be due, in part, to increased renal sympathetic activity. Catheter-based renal denervation (RD) has been reported to lower arterial blood pressure (BP) in humans with resistant hypertension, many of whom are obese. This study was performed to assess the impact of radiofrequency-induced RD on renal function, BP, renal norepinephrine (NE), and histology of nerves along the renal artery in obese, hypertensive dogs, an experimental model that closely mimics cardiorenal and metabolic changes in obese hypertensive humans. METHODS: After control measurements of cardiovascular and renal function were obtained in obese dogs fed a high-fat diet, bilateral RD was performed using the St. Jude Medical EnligHTN RD system. After RD, BP was measured continuously for 8 weeks, and glomerular filtration rate (GFR) was measured biweekly for 6 weeks. At the end of the study, renal arteries were collected for histological analysis, and kidneys were obtained for NE measurement. RESULTS: Eight weeks after RD, systolic BP fell from 157 ± 5 mm Hg pre-RD to 133 ± 3 mm Hg (P < 0.01), and mean arterial pressure decreased by 9 mm Hg compared with pre-RD (P < 0.01). There were no significant changes in GFR. Renal nerve injury was most prevalent 0.28-3.5mm from the renal artery lumen. RD caused injury in 46% of the renal nerves observed and reduced renal tissue NE by 42% (P < 0.01). CONCLUSIONS: Catheter-based RD with the St. Jude Medical EnligHTN system lowers BP in obese dogs without significantly compromising renal function.

Systemic and renal-specific sympathoinhibition in obesity hypertension.

Chronic pressure-mediated baroreflex activation suppresses renal sympathetic nerve activity. Recent observations indicate that chronic electric activation of the carotid baroreflex produces sustained reductions in global sympathetic activity and arterial pressure. Thus, we investigated the effects of global and renal specific suppression of sympathetic activity in dogs with sympathetically mediated, obesity-induced hypertension by comparing the cardiovascular, renal, and neurohormonal responses to chronic baroreflex activation and bilateral surgical renal denervation. After control measurements, the diet was supplemented with beef fat, whereas sodium intake was held constant. After 4 weeks on the high-fat diet, when body weight had increased ≈50%, fat intake was reduced to a level that maintained this body weight. This weight increase was associated with an increase in mean arterial pressure from 100±2 to 117±3 mm Hg and heart rate from 86±3 to 130±4 bpm. The hypertension was associated with a marked increase in cumulative sodium balance despite an approximately 35% increase in glomerular filtration rate. The importance of increased tubular reabsorption to sodium retention was further reflected by ≈35% decrease in fractional sodium excretion. Subsequently, both chronic baroreflex activation (7 days) and renal denervation decreased plasma renin activity and abolished the hypertension. However, baroreflex activation also suppressed systemic sympathetic activity and tachycardia and reduced glomerular hyperfiltration while increasing fractional sodium excretion. In contrast, glomerular filtration rate increased further after renal denervation. Thus, by improving autonomic control of cardiac function and diminishing glomerular hyperfiltration, suppression of global sympathetic activity by baroreflex activation may have beneficial effects in obesity beyond simply attenuating hypertension.

Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics.

BACKGROUND: Lipids have critical functions in cellular energy storage, structure and signaling. Many individual lipid molecules have been associated with the evolution of prostate cancer; however, none of them has been approved to be used as a biomarker. The aim of this study is to identify lipid molecules from hundreds plasma apparent lipid species as biomarkers for diagnosis of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: Using lipidomics, lipid profiling of 390 individual apparent lipid species was performed on 141 plasma samples from 105 patients with prostate cancer and 36 male controls. High throughput data generated from lipidomics were analyzed using bioinformatic and statistical methods. From 390 apparent lipid species, 35 species were demonstrated to have potential in differentiation of prostate cancer. Within the 35 species, 12 were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer with a sensitivity above 80%, specificity above 50% and accuracy above 80%. Using top 15 of 35 potential biomarkers together increased predictive power dramatically in diagnosis of prostate cancer with a sensitivity of 93.6%, specificity of 90.1% and accuracy of 97.3%. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) demonstrated that patient and control populations were visually separated by identified lipid biomarkers. RandomForest and 10-fold cross validation analyses demonstrated that the identified lipid biomarkers were able to predict unknown populations accurately, and this was not influenced by patient's age and race. Three out of 13 lipid classes, phosphatidylethanolamine (PE), ether-linked phosphatidylethanolamine (ePE) and ether-linked phosphatidylcholine (ePC) could be considered as biomarkers in diagnosis of prostate cancer. CONCLUSIONS/SIGNIFICANCE: Using lipidomics and bioinformatic and statistical methods, we have identified a few out of hundreds plasma apparent lipid molecular species as biomarkers for diagnosis of prostate cancer with a high sensitivity, specificity and accuracy.

An enzymatic technique to facilitate air separation of the stroma-Descemet's membrane junction.

PURPOSE: To describe an enzymatic technique that facilitates air separation of Descemet's membrane from the corneal stroma. METHODS: Fresh human corneoscleral tissue was mounted on an artificial anterior chamber. In a control group, air was injected into the stroma. A second group received a stromal injection of 2.5 mg/mL collagenase type 2 in balanced salt solution that was left in the stroma for 1 hour and 15 minutes. A third group received an injection of 2.5 mg/mL collagenase type 2 in balanced salt solution followed 1 hour and 15 minutes later by an injection of air into the stroma. All injections were performed with a 27-gauge needle into the deep stroma without penetrating Descemet's membrane. Anterior segment optical coherence tomography (AS-OCT), histologic examination, and electron microscopy of the junction between the stroma and Descemet's membrane were performed. The trypan blue exclusion and TUNEL assays were used to study endothelial cell viability after collagenase incubation. RESULTS: Injection of air or collagenase into the deep corneal stroma did not result in a reproducible separation of the stroma-Descemet's junction. In contrast, the stroma was easily and reproducibly separated from Descemet's membrane with a combination of intrastromal collagenase and air injection. The separation was confirmed by using light and electron microscopy. The cleavage plane seemed to be located between the junction of the posterior stroma and the anterior banded layer of Descemet's membrane. Trypan blue staining demonstrated the viability of endothelial cells after collagenase incubation. TUNEL assay confirmed excellent viability after collagenase+air separation. CONCLUSIONS: This technique facilitates the separation of Descemet's membrane from the stroma without affecting endothelial cell viability.

Frog virus 3 ORF 53R, a putative myristoylated membrane protein, is essential for virus replication in vitro.

Although previous work identified 12 complementation groups with possible roles in virus assembly, currently only one frog virus 3 protein, the major capsid protein (MCP), has been linked with virion formation. To identify other proteins required for assembly, we used an antisense morpholino oligonucleotide to target 53R, a putative myristoylated membrane protein, and showed that treatment resulted in marked reductions in 53R levels and a 60% drop in virus titers. Immunofluorescence assays confirmed knock down and showed that 53R was found primarily within viral assembly sites, whereas transmission electron microscopy detected fewer mature virions and, in some cells, dense granular bodies that may represent unencapsidated DNA-protein complexes. Treatment with a myristoylation inhibitor (2-hydroxymyristic acid) resulted in an 80% reduction in viral titers. Collectively, these data indicate that 53R is an essential viral protein that is required for replication in vitro and suggest it plays a critical role in virion formation.

Peritoneal inflammation after twenty-week exposure to dialysis solution: effect of solution versus catheter-foreign body reaction.

BACKGROUND: We hypothesized that both sterile solutions and foreign body reaction to the peritoneal dialysis catheter are associated with inflammatory changes in rats exposed to hypertonic solution. METHODS: Four hypertonic solutions (30 - 40 mL) were injected daily via needle and syringe over 20 weeks in 4 groups of rats: 4.25% standard clinical solution (LAC), LAC plus pyridoxamine (PYR), LAC plus ethyl pyruvate (EP), and a biocompatible 4% dextrose solution (BIC). Two groups received catheters: a non-injected 4-week catheter group (C4) and a group injected for 20 weeks with the BIC solution (CI). Control animals (CON) were not injected. In the C4 group, adherent cells were separated from the catheter and examined by culture and electron microscopy to ensure that animals were bacteria free prior to exposure to solution. Animals underwent transport experiments to determine mass transfer coefficients of mannitol (MTC(M)) and albumin (MTC(A)), osmotic filtration flux (J(osm)), and hydrostatic pressure-driven flux (J(p)). After euthanasia, tissues were examined for submesothelial thickness, vascular density, and immunohistochemistry for various cytokines. RESULTS: The catheter cell layer was free of bacteria and consisted of macrophages, lymphocytes, mesothelial cells, and fibroblastic cells. Marked differences in angiogenesis and submesothelial thickening were noted for the catheter groups. Transport differences were mixed: MTC(M) was significantly less for the CI group and MTC(A) was variable among the groups. There were no differences among groups for J(osm) or J(p). Inflammatory markers in the catheter-adherent cells correlated with inflammatory changes in the tissue. These data demonstrate significant changes in submesothelial thickness, angiogenesis, transport function, and inflammatory markers between animals injected with sterile solutions over 20 weeks with and without catheters. CONCLUSION: An indwelling catheter amplifies peritoneal inflammation from dialysis solutions through a foreign body reaction. Our data also suggest that additives to existing solutions may have limited the effect on inflammatory response to non-biocompatible solutions.

Peritoneal changes after exposure to sterile solutions by catheter.

Most current animal models that are used to study effects of long-term peritoneal exposure to dialysis solutions use an indwelling catheter for daily injections. It was hypothesized that the presence of a foreign body in the peritoneal cavity (PC) might alter the inflammatory response to the solutions and that the response would depend on exposure duration. For addressing these, long-term injections were carried out for 2 to 8 wk in 90 Sprague-Dawley rats: 40 via a subcutaneous port connected to a silicone catheter tunneled to the PC, 40 via direct needle injection, and 10 noninjected, age-control rats. Daily volumes were 30 to 40 ml of filter-sterilized, bicarbonate-buffered solutions that contained 4% dextrose. After 2, 4, 6, and 8 wk, anesthetized rats underwent transport experiments with a chamber affixed to the abdominal wall to determine mass transfer coefficients of mannitol (MTC(mannitol)) and albumin (MTC(BSA)), osmotic filtration flux (J(osm)), and hydrostatic pressure-driven flux. After the rats were killed, tissues were collected for measurement of peritoneal thickness, vascular density, and immunohistochemical staining. ANOVA demonstrated significant (P < 0.01) differences in thickness, vessel density, MTC(mannitol), and MTC(BSA) among the groups at the various time intervals and in overall means. Differences among the groups were less pronounced for hydrostatic pressure-driven flux and J(osm). Vessel density, MTC(mannitol), MTC(BSA), and J(osm) were dependent on injection duration (P < 0.01). There were marked differences between the needle injection and catheter injection groups at various intervals in the expression of three cytokines. It is concluded that the histologic and functional response depends on the duration of injection with animals that are exposed for as little as 2 wk demonstrating alterations. These findings confirm the hypothesis that the presence of a PC catheter increases inflammatory response to sterile solutions as evidenced by the structural and functional changes in the peritoneal barrier.

Correlating structure with solute and water transport in a chronic model of peritoneal inflammation.

To study the process of chronic peritoneal inflammation from sterile solutions, we established an animal model to link structural changes with solute and water transport. Filtered solutions containing 4% N-acetylglucosamine (NAG) or 4% glucose (G) were injected intraperitoneally daily in 200- to 300-g rats and compared with controls (C). After 2 mo, each animal underwent transport studies using a chamber affixed to the parietal peritoneum to determine small-solute and protein mass transfer, osmotic filtration, and hydraulic flow. After euthanasia, parietal tissues were sampled for histological analysis, which demonstrated significant differences in peritoneal thickness (microm; C, 42.6 +/- 7.5; G, 80.4 +/- 22.3; NAG, 450 +/- 104; P < 0.05). Staining for VEGF correlated with CD-31 vessel counts (no./mm2: C, 53.1 +/- 16.1; G, 166 +/- 32; NAG, 183 +/- 32; P < 0.05). Tissue analysis showed treatment effects on tissue hyaluronan (micro/g: C, 962 +/- 73; G, 1,169 +/- 69; NAG, 1,428 +/- 69; P < 0.05) and collagen (microg/g: C, 56.9 +/- 12.0; G, 107 +/- 12; NAG, 97.6 +/- 11.4; P < 0.05) but not sulfated glycosaminoglycan. Transport experiments revealed no significant differences in mannitol transfer or osmotic flow. Changes were seen in hydrostatic pressure-driven flux (microl x min(-1) x cm(-2): C, 0.676 +/- 0.133; G, 0.317 +/- 0.124; NAG, 0.284 +/- 0.117; P < 0.05) and albumin transfer (microl x min(-1) x cm(-2): C, 0.331 +/- 0.028; G, 0.286 +/- 0.026; NAG, 0.229 +/- 0.025; P < 0.04). We conclude that alteration of the interstitial matrix correlates with diminished hydraulic conductivity and macromolecular transport.

Glial S100B Positive Vacuoles In Purkinje Cells: Earliest Morphological Abnormality In SCA1 Transgenic Mice.

Spinocerebellar ataxia-1 (SCA1) is caused by the expansion of a polyglutamine repeat within the disease protein, ataxin-1. The overexpression of mutant ataxin-1 in SCA1 transgenic mice results in the formation of cytoplasmic vacuoles in Purkinje neurons (PKN) of the cerebellum. PKN are closely associated with neighboring Bergmann glia. To elucidate the role of Bergmann glia in SCA1 pathogenesis, cerebellar tissue from 7 days to 6 wks old SCA1 transgenic and wildtype mice were used. We observed that Bergmann glial S100B protein is localized to the cytoplasmic vacuoles in SCA1 PKN. These S100B positive cytoplasmic vacuoles began appearing much before the onset of behavioral abnormalities, and were negative for other glial and PKN marker proteins. Electron micrographs revealed that vacuoles have a double membrane. In the vacuoles, S100B colocalized with receptors of advanced glycation end-products (RAGE), and S100B co-immunoprecipated with cerebellar RAGE. In SCA1 PKN cultures, exogenous S100B protein interacted with the PKN membranes and was internalized. These data suggest that glial S100B though extrinsic to PKN is sequestered into cytoplasmic vacuoles in SCA1 mice at early postnatal ages. Further, S100B may be binding to RAGE on Purkinje cell membranes before these membranes are internalized.

Glomerular calcification in hypercalcemic nephropathy.

Hypercalcemic nephropathy has been classified as a tubulointerstitial renal disease. The presence of glomerular pathologic findings attributable to hypercalcemia has been observed in only a few patients and therefore has been considered an unusual finding. In the current study, calcium deposition within glomeruli was investigated in 2 patients with extreme elevations in serum calcium levels and hypercalcemic nephropathy. The study material consisted of a renal biopsy specimen from a 31-year-old woman (patient 1) who had T-cell lymphoma/leukemia and a serum calcium level of 20.2 mg/dL (5.0 mmol/L) and autopsy kidney specimens from a 19-year-old woman (patient 2) who was being evaluated for primary hyperparathyroidism and a calcium level of 18.4 mg/dL (4.6 mmol/L). The renal biopsy specimen for patient 1 exhibited calcium deposits present in the glomerular capillary basement membranes, where they were associated with segmental sclerosing lesions (21% of glomeruli). Nine percent of the cortical tubules contained calcifications. In patient 2, calcium was found in the mesangial areas in 95% of glomeruli, filling the Bowman space in 7% of glomeruli, or associated with capillary basement membranes and segmental sclerosing lesions (12% of glomeruli). Fifteen percent of cortical tubules, 4% of outer medullary tubules, and 40% of inner medullary tubules were calcified. In neither case was there immunofluorescence or electron microscopic evidence of primary glomerular disease. Thus, glomerular calcification may exceed that occurring in the cortical and outer medullary tubules and may play a significant role in the loss of renal function in hypercalcemic nephropathy. Glomerular calcinosis may also be recognized as an additional cause of segmental glomerulosclerosis and nephrotic range proteinuria in patients with extremely high levels of serum calcium.

Cytochrome P450 2B1 mediates oxidant injury in puromycin-induced nephrotic syndrome.

BACKGROUND: Reactive oxygen metabolites (ROM) are important mediators of puromycin aminonucleoside (PAN) induced minimal change nephrotic syndrome (NS) in rats. We have recently shown that cytochrome P450 (CYP) is a significant source of catalytic iron in this model of glomerular injury. The current study was designed to identify the CYP isozyme(s) in the rat glomeruli and explore the role of the specific isozyme(s) in PAN-induced minimal change NS. METHODS: NS was induced in rats by a single intravenous injection of PAN. Animals were sacrificed at different time points for variety of biochemical assays including Western blot, immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Ultrastructural histochemistry was utilized to study hydrogen peroxide (H2O2) generation in the kidney. RESULTS: Several CYP isozymes were tested and CYP2B1 was localized exclusively in the rat glomeruli but not in the tubules. Treatment with PAN resulted in the generation of H2O2 in the glomerular basement membrane with significant loss of CYP2B1 content accompanied by a marked increase in the catalytic iron. CYP2B1 inhibitors cimetidine and piperine significantly reduced H2O2 generation, and prevented the loss of CYP2B1 content and the increase in the catalytic iron. CYP2B1 inhibitors also provided significant protection against PAN induced proteinuria. The induction of heme oxygenase and ferritin also was observed in the glomeruli in PAN-treated rats. Both cimetidine and piperine reduced the up-regulation of these proteins. CONCLUSION: Our data indicate that CYP2B1 plays an important role in PAN induced NS by serving as a site for ROM generation and a significant source of catalytic iron.

Functional and structural changes in the kidney in the early stages of obesity.

The purpose of this study was to examine the histologic and functional changes that occur in the kidney in the early stages of obesity caused by a high-fat diet. Lean dogs (n = 8) were fed a standard kennel ration, and obese dogs (n = 8) were fed the standard kennel ration plus a supplement of cooked beef fat each day for 7 to 9 wk or 24 wk. Body weights were 58 +/- 5% greater and kidney weights were 31 +/- 7% greater in obese dogs, compared with the average values for lean dogs. Plasma renin activity and insulin concentrations were both 2.3-fold greater in obese dogs, compared with lean dogs. Obesity was associated with a mean arterial pressure increase of 12 +/- 3 mmHg, a 38 +/- 6% greater GFR, and a 61 +/- 7% higher renal plasma flow, compared with lean dogs. The glomerular Bowman's space area was significantly greater (+41 +/- 7%) in dogs fed the high-fat diet, compared with lean animals, mainly because of expansion of Bowman's capsule (+22 +/- 7%). There was also increased mesangial matrix and thickening of the glomerular and tubular basement membranes and the number of dividing cells (proliferating cell nuclear antigen-stained) per glomerulus was 36 +/- 8% greater in obese dogs, compared with lean dogs. There was also a trend for glomerular transforming growth factor-beta1 expression, as estimated by semiquantitative immunohistochemical analysis, to be elevated with the high-fat diet. Therefore, a high-fat diet caused increased arterial pressure, hyperinsulinemia, activation of the renin-angiotensin system, glomerular hyperfiltration, and structural changes in the kidney that may be the precursors of more severe glomerular injury associated with prolonged obesity.

Apoptosis in the left ventricle of chronic volume overload causes endocardial endothelial dysfunction in rats.

The hypothesis is that chronic increases in left ventricular (LV) load induce oxidative stress and latent matrix metalloproteinase (MMP) is activated, allowing the heart to dilate in the absence of endothelial nitric oxide (NO) and thereby reduce filling pressure. To create volume overload, an arteriovenous (A-V) fistula was placed in male Sprague-Dawley rats. To decrease oxidative stress and apoptosis, 0.08 mg/ml nicotinamide (Nic) was administered in drinking water 2 days before surgery. The rats were divided into the following groups: 1) A-V fistula, 2) A-V fistula + Nic, 3) sham operated, 4) sham + Nic, and 5) control (unoperated); n = 6 rats/group. After 4 wk, hemodynamic parameters were measured in anesthetized rats. The heart was removed and weighed, and LV tissue homogeneates were prepared. A-V fistula caused an increase in heart weight, lung weight, and end-diastolic pressure compared with the sham group. The levels of malondialdehyde (MDA; a marker of oxidative stress) was 6.60 +/- 0.23 ng/mg protein and NO was 6.87 +/- 1.21 nmol/l in the LV of A-V fistula rats by spectrophometry. Nic treatment increased NO to 13.88 +/- 2.5 nmol/l and decreased MDA to 3.54 +/- 0.34 ng/mg protein (P = 0.005). Zymographic levels of MMP-2 were increased, as were protein levels of nitrotyrosine and collagen fragments by Western blot analysis. The inhibition of oxidative stress by Nic decreased nitrotyrosine content and MMP activity. The levels of tissue inhibitor of metalloproteinase-4 mRNA were decreased in A-V fistula rats and increased in A-V fistula rats treated with Nic by Northern blot analysis. TdT-mediated dUTP nick-end labeling-positive cells were increased in A-V fistula rats and decreased in fistula rats treated with Nic. Acetylcholine and nitroprusside responses in cardiac rings prepared from the above groups of rats suggest impaired endothelial-dependent cardiac relaxation. Treatment with Nic improves cardiac relaxation. The results suggest that an increase in the oxidative stress and generation of nitrotyrosine are, in part, responsible for the activation of metalloproteinase and decreased endocardial endothelial function in chronic LV volume overload.

Is obesity a major cause of chronic kidney disease?

Excess weight gain is a major risk factor for essential hypertension and for end-stage renal disease (ESRD). Obesity raises blood pressure by increasing renal tubular sodium reabsorption, impairing pressure natriuresis, and causing volume expansion because of activation of the sympathetic nervous system and renin-angiotensin system and by physical compression of the kidneys, especially when visceral obesity is present. Obesity also causes renal vasodilation and glomerular hyperfiltration that initially serve as compensatory mechanisms to maintain sodium balance in the face of increased tubular reabsorption. In the long-term, however, these changes, along with the increased systemic arterial pressure, create a hemodynamic burden on the kidneys that causes glomerular injury. With prolonged obesity, there is increasing urinary protein excretion and gradual loss of nephron function that worsens with time and exacerbates hypertension. With the worsening of metabolic disturbances and the development of type II diabetes in some obese patients, kidney disease progresses much more rapidly. Weight reduction is an essential first step in the management of obesity, hypertension, and kidney disease. Special considerations for the obese patient, in addition to adequately controlling the blood pressure, include correction of the metabolic abnormalities and protection of the kidneys from further injury.