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[Display omitted] [ABSTRACT FROM AUTHOR]

Interatrial block (IAB) is an electrocardiographic pattern describing the conduction delay between the right and left atria. IAB is classified into 3 degrees of block that correspond to decreasing conduction in the region of Bachmann's bundle. Although initially considered benign in nature, specific subsets of IAB have been associated with atrial arrhythmias, elevated thromboembolic stroke risk, cognitive impairment, and mortality. As the pathophysiologic relationships between IAB and stroke are reinforced, investigation has now turned to the potential benefit of early detection, atrial imaging, cardiovascular risk factor modification, antiarrhythmic pharmacotherapy, and stroke prevention with oral anticoagulation. This review provides a contemporary overview of the epidemiology, pathophysiology, diagnosis, and management of IAB, with a focus on future directions. [ABSTRACT FROM AUTHOR]

Myocardial bridging (MB) is a congenital coronary anomaly in which a segment of the epicardial coronary artery traverses through the myocardium for a portion of its length. The muscle overlying the artery is termed a myocardial bridge, and the intramyocardial segment is referred to as a tunneled artery. MB can occur in any coronary artery, although is most commonly seen in the left anterior descending artery. Although traditionally considered benign in nature, increasing attention is being given to specific subsets of MB associated with ischemic symptomatology. The advent of contemporary functional and anatomic imaging modalities, both invasive and noninvasive, have dramatically improved our understanding of dynamic pathophysiology associated with MBs. This review provides a contemporary overview of epidemiology, pathobiology, diagnosis, functional assessment, and management of MBs. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the prevalence and prognostic impact of high bleeding risk (HBR), as determined by the Academic Research Consortium HBR criteria, in real-world patients undergoing left main (LM) percutaneous coronary intervention (PCI). LM PCI is often reserved for patients at increased risk for periprocedural adverse events. Patients at HBR represent a relevant percentage of this cohort, but their outcomes after LM PCI are still poorly investigated. All patients undergoing LM PCI between 2014 and 2017 at a tertiary care center were prospectively enrolled. Patients were defined as having HBR if they met at least 1 major or 2 minor Academic Research Consortium HBR criteria. The primary endpoint was the composite of all-cause death, myocardial infarction (MI), or stroke at 12 months. Among 619 enrolled patients, 55.3% were at HBR. The rate of the primary endpoint was 4-fold higher in patients at HBR compared with those without HBR (20.5% vs 4.9%; HR: 4.43; 95% CI: 2.31-8.48), driven by an increased risk for all-cause death (HR: 3.88; 95% CI: 1.88-8.02) and MI (HR: 6.18; 95% CI: 1.83-20.9). Rates of target vessel or lesion revascularization and stent thrombosis were comparable in the 2 groups. Bleeding occurred more frequently in patients at HBR (HR: 3.77; 95% CI: 1.83-7.76). Consistent findings were observed after Cox multivariable regression adjustment. Among patients undergoing LM PCI, those with HBR are at increased risk for all-cause death, MI, and bleeding. Conversely, rates of repeat revascularization and stent thrombosis were comparable, suggesting frailty and comorbidities as primary causes of worse outcomes in patients at HBR. [Display omitted] [ABSTRACT FROM AUTHOR]

The impact of diabetes mellitus (DM) on clinical outcomes after transcatheter aortic valve replacement (TAVR) remains unclear. The aim of this study was to investigate the impact of DM on short-term clinical outcomes after TAVR in a large randomized trial population. BRAVO-3 trial randomized 802 patients undergoing trans -femoral TAVR to procedural anticoagulation with bivalirudin or unfractionated heparin. The study population was divided according to the presence of DM, and further stratified according to the use of insulin. Net adverse cardiovascular outcomes (NACE – death, myocardial infarction (MI), stroke or major bleeding by Bleeding Academic Research Consortium (BARC) type 3b or above) was the primary outcome in-hospital and at 30-days. Of the total 802 randomized patients, 239 (30%) had DM at baseline, with 87 (36%) being treated with insulin. At 30-days, DM patients experienced numerically higher rates of net adverse cardiovascular events (16.3% vs. 14.4%, p = 0.48) and acute kidney injury (19.7% vs. 15.1%, p = 0.11), while non-DM (NDM) patients had numerically higher rates of cerebrovascular accidents (3.6% vs. 1.7%, p = 0.22). After multivariable adjustment, DM patients had higher odds of vascular complications at 30-days (OR 1.57, p = 0.03) and life-threatening bleeding both in-hospital (OR 1.50, p = 0.046) and at 30-days (OR 1.50, p = 0.03) with the excess overall risk primarily attributed to the higher rates observed among non-insulin dependent DM patients. Patients with DM had higher adjusted odds of vascular and bleeding complications up to 30-days post-TAVR. Overall, there was no significant association between DM and early mortality following TAVR. • DM patients undergoing TAVR are at higher risk of life-threatening bleeding. • DM patients are also at higher risk of major vascular complication after TAVR. • Insulin dependent DM doesn't increase risk for short-term adverse events after TAVR. • DM does not increase risk of short-term mortality following trans -femoral TAVR. [ABSTRACT FROM AUTHOR]

Transcatheter aortic valve replacement (TAVR) is a validated treatment option for severe aortic stenosis. Ischemic and thrombotic complications remain important and strongly correlate with mortality. The optimal postprocedural antithrombotic strategy for prevention of thrombotic events remains unclear. The international guidelines for medical management following TAVR are discordant, allowing for significant variance in prescribing habits. The optimal treatment strategy has yet to be delineated. Clinical trials are ongoing to assess the risks and benefits of various strategies. We discuss the pathobiology and rationale for antithrombotic therapy after TAVR, review current evidence and guidelines, and offer a concise evidence-based approach to this subject. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Persisting at a task can temporarily reduce one’s ability to persist at subsequent tasks. This phenomenon is known as “ego depletion”. Although ego depletion has been linked to many cognitive tasks less is known about its effect on physical tasks. Even less is known about its effect on practiced physical performance associated with athletes. In modern sport science, the question as to whether or not ego depletion can reduce athletes’ persistence at practiced behaviour should be particularly important. Two experimental studies investigated if ego depletion can reduce athletes’ persistence at a routine physical exercise. Design: In both experiments, a repeated measures design was employed. Method: Competitive rowers (Experiment 1) and competitive hockey and rugby players (Experiment 2) attempted to complete as many press-ups (Experiment 1) or sit-ups (Experiment 2) as possible over two separate phases. In one phase, the participants attempted the physical exercise after completing an easy cognitive task. In the other phase, they attempted the physical exercise after completing a difficult cognitive task. Results: Experiment 1 demonstrated that the competitive rowers completed fewer press-ups after completing a difficult cognitive task than they did after completing an easy task. Experiment 2 demonstrated that the competitive hockey and rugby players completed fewer sit-ups after completing a difficult cognitive task than they did after completing an easy cognitive task. Conclusions: These findings indicate that athletes’ exercise routines are susceptible to ego depletion and that the strength model of self-regulation is applicable to athletic performance. [Copyright &y& Elsevier]

Abstract: A remarkably concise, chromatography-free route to the parent compound of the paullone family of cyclin-dependent kinase (CDK) inhibitors is reported. A similar strategy allowed the synthesis of the hitherto missing 9-azapaullone and its protonated, N-oxidised and N-alkylated derivatives. Screening studies identified an active and strongly selective inhibitor of CDK9/cyclin T. [ABSTRACT FROM AUTHOR]

Most individuals with thin basement membrane nephropathy (TBMN) have an excellent prognosis. For these patients, the only hazards are the anxiety related to misconceptions about the diagnosis and the inconvenience, expense, and wastefulness of unnecessary investigations. However, there also are specific genetic implications for individuals with TBMN because, on average, half their offspring inherit the causative mutations and most of these have hematuria. In addition, despite the generally excellent outcome, some individuals with TBMN develop hypertension, proteinuria, or renal impairment. In some cases, renal failure is caused by apparently progressive but otherwise uncomplicated TBMN, and in others it results from a secondary or coincidental glomerular or tubulointerstitial renal lesion. In particular, TBMN appears to predispose to immunoglobulin (Ig)A glomerulonephritis, and the outcome for these patients is worse than for those with TBMN alone. The risks for patients with TBMN in relation to pregnancy and transplantation have not been well-studied but are described elsewhere in this issue. [ABSTRACT FROM AUTHOR]

Highlights: [•] The often quoted statistic for patient safety relates only to hospital inpatients. [•] Following a decade of initiatives avoidable errors show little change. [•] Primary care studies show different errors to those recorded in hospitals. [Copyright &y& Elsevier]

Acute kidney injury (AKI) disrupts energy metabolism. Targeting metabolism through AMP-activated protein kinase (AMPK) may alleviate AKI. ATX-304, a pan-AMPK activator, was evaluated in C57Bl/6 mice and tubular epithelial cell (TEC) cultures. Mice received ATX-304 (1 mg/g) or control chow for 7 days before cisplatin-induced AKI (CI-AKI). Primary cultures of tubular epithelial cells (TECs) were pre-treated with ATX-304 (20 µM, 4 h) prior to exposure to cisplatin (20 µM, 23 h). ATX-304 increased acetyl-CoA carboxylase phosphorylation, indicating AMPK activation. It protected against CI-AKI measured by serum creatinine (control 0.05 + 0.03 mM vs ATX-304 0.02 + 0.01 mM, P = 0.03), western blot for neutrophil gelatinase-associated lipocalin (NGAL) (control 3.3 + 1.8-fold vs ATX-304 1.2 + 0.55-fold, P = 0.002), and histological injury (control 3.5 + 0.59 vs ATX-304 2.7 + 0.74, P = 0.03). In TECs, pre-treatment with ATX-304 protected against cisplatin-mediated injury, as measured by lactate dehydrogenase release, MTS cell viability, and cleaved caspase 3 expression. ATX-304 protection against cisplatin was lost in AMPK-null murine embryonic fibroblasts. Metabolomic analysis in TECs revealed that ATX-304 (20 µM, 4 h) altered 66/126 metabolites, including fatty acids, tricarboxylic acid cycle metabolites, and amino acids. Metabolic studies of live cells using the XFe96 Seahorse analyzer revealed that ATX-304 increased the basal TEC oxygen consumption rate by 38%, whereas maximal respiration was unchanged. Thus, ATX-304 protects against cisplatin-mediated kidney injury via AMPK-dependent metabolic reprogramming, revealing a promising therapeutic strategy for AKI. [Display omitted] • Activation of AMPK by ATX-304 protected against cisplatin-mediated kidney injury. • AMPK dependence of protection against cisplatin injury was shown in AMPK KO MEFs. • Metabolome analysis revealed widespread changes in ATX-304 treated kidney cells. • Respiration and glycolysis in live kidney cells increased after ATX-304 treatment. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the most common cause of death in patients with end-stage renal disease (ESRD). The initiation of dialysis for treatment of ESRD exacerbates chronic electrolyte and hemodynamic perturbations. Rapid large shifts in effective intravascular volume and electrolyte concentrations ultimately lead to subendocardial ischemia, increased left ventricular wall mass, and diastolic dysfunction, and can precipitate serious arrhythmias through a complex pathophysiological process. These factors, unique to advanced kidney disease and its treatment, increase the overall incidence of acute coronary syndrome and sudden cardiac death. To date, risk prediction models largely fail to incorporate the observed cardiovascular mortality in the CKD population; however, multimodality imaging may provide an additional prognostication and risk stratification. This comprehensive review discusses the cardiovascular risks associated with hemodialysis, and explores the pathophysiology and the novel utilization of multimodality imaging in CKD to promote a personalized approach for these patients with implications for future research. [ABSTRACT FROM AUTHOR]

Female subjects constitute half of all transcatheter aortic valve implantation (TAVI) candidates, but the association between important comorbidities such as diabetes mellitus (DM) and clinical outcomes after TAVI remains unclear in this group. WIN-TAVI is a real-world international registry of exclusively female subjects undergoing TAVI. The study population was stratified into those with (DM) and those without DM (NDM). Valve Academic Research Consortium (VARC)-2 efficacy (composite of all-cause death, stroke, myocardial infarction, hospitalization for valve-related symptoms or worsening congestive heart failure, or valve-related dysfunction) was the primary endpoint for this analysis. Of the 1012 subjects included in this study, 264 (26.1%) had DM at baseline. DM patients were younger but had a higher burden of comorbidities. There were no differences in VARC-2 efficacy events between DM and NDM patients at 30 days or 1 year. Conversely, patients with DM had a lower risk of VARC-2 life threatening bleeding at 30 days and 1 year after TAVI compared to NDM patients, which remained significant even after multivariable adjustment (HR, 0.34, 95% CI, 0.12–0.99; p =.047). In the subgroup analysis, insulin-dependent DM was not associated with an increased risk of adverse outcomes. Among female patients undergoing TAVI, more than one-fourth of the subjects presented with DM. At 1-year follow-up, DM was associated with lower bleeding complications and no increase in the risk of other adverse events, including mortality, after TAVI. Unlabelled Image • One fourth of female subjects undergoing transcatheter aortic valve implantation have diabetes mellitus at baseline. • DM female patients undergoing TAVI have higher comorbidities and lower transvalvular gradients. • DM in female subjects is associated with lower risk of VARC-2 life threatening bleeding up to 1 year after TAVI. [ABSTRACT FROM AUTHOR]

The risk of stent thrombosis (ST) or target lesion revascularization (TLR) is increased with smaller stent diameters (SD). Whether SD has a deleterious effect in women treated with early- vs. new-generation drug-eluting stents (DES) is unknown. We pooled patient-level data from 26 randomized control trials of DES. Only women treated with DES were included. Subjects were stratified according to SD: small, SD ≤ 2.75 mm; intermediate, 2.75 mm < SD ≤ 3.25 mm; and large, SD ≥ 3.25 mm. Endpoints of interest were 3-year definite ST, TLR, major adverse cardiac events (MACE: the composite of death, myocardial infarction or TLR) and death. Of 6413 women, 2274 (35.0%) had a small SD, 2448 (38.0%) had an intermediate SD, and 1691 (26.0%) had a large SD. By multivariable analysis, stent diameter (per 0.25 mm decrease) was associated with an increased risk of TLR and ST, which was uniform in terms of magnitude and direction between early- and new-generation DES. There were no differences in MACE or death across groups. Small SD in women undergoing PCI is associated with an increased risk of definite ST and TLR, consistently with both early- and new-generation DES. • First report of the effects of SD and DES generation from a female-only cohort • Smaller stents are associated with adverse ischemic events following PCI in women. • Effects of stent diameter are consistent with both early- and new-generation DES. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is accompanied by dysregulation of cellular energy metabolism and accumulation of intracellular lipid. Phosphorylation of acetyl-CoA carboxylase (ACC) by AMP-activated protein kinase (AMPK) inhibits fatty acid synthesis and promotes fatty acid oxidation (FAO), vital for kidney tubular epithelial cells (TECs). The diabetes drug metformin is protective in models of AKI; however, it is not known whether ACC phosphorylation plays a role. Cisplatin-induced AKI (CI-AKI) was established in ACC1/2 double knock-in (ACC1/2DKI) mice, harbouring mutations that disrupt fatty acid metabolism, and the role of metformin was studied in this model. Outcomes measured included serum biochemistry, expression of kidney injury markers such as neutrophil gelatinase-associated lipocalin (NGAL), and metabolomic analysis. ACC1/2DKI mice demonstrated more severe CI-AKI than wild type (WT), as assessed by serum urea and creatinine, histological injury, and expression of NGAL and interleukin-6. Metformin protected against AKI in WT mice, shown by reduced NGAL, but this effect was absent in ACC1/2DKI mice. In cultured TECs exposed to cisplatin, metformin reduced expression of cleaved caspase-3, however, this effect was diminished in ACC1/2DKI TECs. Analysis of kidney polar metabolites found numerous differences between metformin-treated CI-AKI in ACC1/2DKI and WT mice, involving multiple pathways of amino acid, nucleoside, and energy metabolism. Severity of CI-AKI is exacerbated by the inability to regulate metabolism via phosphorylation of ACC. ACC phosphorylation contributes to the protective effect of metformin against AKI, influencing multiple mechanisms involved in the pathogenesis of kidney injury. [Display omitted] • Blocking phosphorylation of ACC by AMPK increased severity of acute kidney injury. • ACC phosphorylation by AMPK contributed to metformin's protection against AKI. • Metabolomics analysis revealed widespread metabolic alterations with kidney injury. • The kynurenine pathway was markedly disrupted with cisplatin induced kidney injury. • Fatty acid metabolism is a promising target for addressing acute kidney injury. [ABSTRACT FROM AUTHOR]

AMG 416 (velcalcetide), a novel peptide agonist of the calcium-sensing receptor, lowers plasma parathyroid hormone in preclinical uremic animal models and in normal healthy individuals. Here, we studied its efficacy in hemodialysis patients suffering from secondary hyperparathyroidism. Major inclusion criteria were hemodialysis for at least 3 months, serum parathyroid hormone over 300 pg/ml, a corrected serum calcium of 9.0 mg/dl or more, and stable doses of vitamin D analogs for at least 3 weeks prior to screening. Twenty-eight patients were enrolled in one of five cohorts (5, 10, 20, 40, 60 mg). Cohorts 1-3 (four patients each) were treated in a two-period crossover design, while cohorts 4 and 5 (eight patients each) were randomized 1:1 to AMG 416 or placebo. Patients were admitted to a clinical research unit following hemodialysis and studied for 3 days prior to discharge for hemodialysis. Single intravenous doses of AMG 416 from 5 to 60 mg were well tolerated, and plasma levels increased in a dose-related manner. AMG 416 treatment was associated with significant, dose-dependent reductions in serum parathyroid hormone and fibroblast growth factor 23. Compared with placebo, all dose groups of 10 mg or more were associated with attenuation in the rise in serum phosphate during the interdialytic period. Dose-dependent reductions in serum calcium were observed and were well tolerated. Thus, AMG 416 represents a novel therapeutic approach for the treatment of secondary hyperparathyroidism in hemodialysis patients. [ABSTRACT FROM AUTHOR]

Abstract: Endothelial cell lipotoxicity mediated by accumulation of free fatty acids is an early event in the pathogenesis of atherosclerosis. The energy-sensor AMP-activated protein kinase (AMPK) is a key regulator of endothelial cell lipid metabolism. To test the hypothesis that bradykinin (BK) regulates AMPK and fatty acid oxidation in endothelium, stimulations of bovine aortic endothelial cells (BAECs) with bradykinin were performed. BK stimulation caused a 2.3-fold increase in AMPK activity (p <0.05). Activation of AMPK by BK in BAECs was inhibited by STO-609, an inhibitor of calmodulin-dependent kinase kinase (CaMKK), which is a known kinase upstream of AMPK. BK stimulation of BAECs also increased phosphorylation of acetyl-CoA carboxylase and this was inhibited by both STO-609 and over expression of an adenovirus encoded AMPK dominant negative (Ad-AMPK-DN). Furthermore, BK caused a 1.7-fold increase in palmitate oxidation in BAECs (p <0.05) and this increase was completely inhibited by the Ad-AMPK-DN (p <0.005). Inhibition of AMPK activation in response to BK by STO-609 had no effect on activating phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177, consistent with CaMKK and AMPK not being required for phosphorylation of eNOS in response to BK. In conclusion, BK stimulates endothelial cell fatty acid oxidation by CaMKK-dependent activation of AMPK. The effect of BK on endothelial lipid metabolism represents a novel pathway for targeting fatty acid mediated endothelial cell dysfunction. [Copyright &y& Elsevier]

The increased incidence of pure red cell aplasia with an Eprex formulation in uncoated rubber stopper syringes.Background.The incidence of pure red cell aplasia (PRCA) in chronic kidney disease patients treated with epoetins increased substantially in 1998, was shown to be antibody mediated, and was associated predominantly with subcutaneous administration of Eprex®. A technical investigation identified organic compounds leached from uncoated rubber stoppers in prefilled syringes containing polysorbate 80 as the most probable cause of the increased immunogenicity.Methods.This study investigated whether the incidence of PRCA was higher for exposure to the product form containing leachates than for leachate-free product forms. Antibody-mediated PRCA cases were classified according to indication, product form, and route of administration. Exposure estimates were obtained by country, indication, route of administration, and product form.Results.For 2001 to 2003, the PRCA incidence rate for patients with subcutaneous exposure to Eprex in prefilled syringes with polysorbate 80 and uncoated rubber stoppers (leachates present) was 4.61/10,000 patient years (95% CI 3.88–5.43) versus 0.26/10,000 patient years (95% CI 0.007–1.44) for syringes with coated stoppers (leachates absent). The rate difference was 4.35/10,000 patient years (95% CI 3.44–5.26;P<0.0001); the rate ratio was 17 (95% CI 3.14–707). A substantial rate difference remained in sensitivity analyses that adjusted for exposure to multiple product forms.Conclusion.The epidemiologic data, together with the chemical and immunologic data, support the hypothesis that leachates from uncoated rubber syringe stoppers caused the increased incidence of PRCA associated with Eprex. Currently, all Eprex prefilled syringes contain fluoro-resin coated stoppers, which has contributed to decreased incidence of PRCA with continued surveillance. [ABSTRACT FROM AUTHOR]

Rare cases of unexplained sudden severe anemia or red cell aplasia and resistance to recombinant human erythropoietin (rHuEPO) in patients with chronic renal failure (CRF) have been attributed to the development of anti-EPO antibodies. The development and validation of a radioimmunoprecipitation (RIP) assay to detect human anti-EPO antibodies in serum or plasma has been hampered by the lack of purified antibody to fully characterize and validate the assay. We have prepared an affinity-purified human antibody to EPO and used the antibody to characterize and validate a sensitive and reproducible RIP assay that can qualitatively measure anti-EPO antibody in serum or plasma samples. The lower limit of detection of the assay is 8 ng/ml of purified antibody. The threshold for detecting antibody is ≥0.9% cpm bound. The precision of the assay using purified antibody standards ranges from 5.8% to 15.3% and the precision of the assay using dilutions of the positive control ranges from 15.9% to 18.7%. EPO in the samples did not interfere with detection of the anti-EPO antibody except at high concentrations. [Copyright &y& Elsevier]

Renal ischemia-reperfusion increases endothelial VEGFR-2 without increasing VEGF or VEGFR-1 expression. Background. Hypoxia is a potent stimulus to angiogenesis. Expression of the angiogenic growth factor vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1 and VEGFR-2) is up-regulated by hypoxia in a variety of organs and cell lines. We have previously reported that VEGF expression is not increased in renal ischemia-reperfusion injury, although tubular cells concentrate VEGF at their basolateral surface. In this study we assess whether altered VEGF receptor expression compensates for the lack of VEGF regulation during renal ischemia-reperfusion injury. Methods. VEGFR-1 mRNA expression was assessed by Northern blotting and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). VEGFR-2 mRNA expression was analyzed by Northern blotting and in situ hybridization (ISH), while VEGFR-2 protein expression was studied using immunohistochemistry. VEGF mRNA expression was assessed by ISH. Results. VEGFR-2 mRNA and protein expression were up-regulated without an increase in VEGF or VEGFR-1 expression. Normal kidneys showed low-level VEGFR-2 mRNA and protein expression in glomerular and peritubular endothelium. Following ischemia and ischemia-reperfusion, a marked increase in VEGFR-2 mRNA and protein expression was seen (2- to 4-fold). Most prominent was VEGFR-2 mRNA up-regulation in the glomerulus although, surprisingly, increased protein was not demonstrated here. ISH showed that VEGF mRNA was not up-regulated in this model, confirming our previous findings for VEGF. Conclusion. VEGF and VEGFR-1 expression are not increased by renal ischemia and ischemia-reperfusion injury. Instead, endothelial expression of VEGFR-2 is increased. VEGFR-2 up-regulation in renal ischemia-reperfusion may be important in mediating the mitogenic and anti-apoptotic actions of VEGF on endothelial cells, thereby preserving the integrity of the endothelium and... [ABSTRACT FROM AUTHOR]

Increased expression of heparanase in puromycin aminonucleoside nephrosis. Background. The β-D-endoglycosidase heparanase has been proposed as an important contributor to loss of glomerular charge in proteinuria. Expression of heparanase was, therefore, determined in acute puromycin aminonucleoside (PAN) nephrosis. Methods. A rabbit polyclonal antibody was produced against a 17-amino acid peptide derived from the predicted amino acid sequence of heparanase. The antibody was validated by Western blot. Immunohistochemical staining and Western blotting were used to localize heparanase protein in normal kidneys and kidneys from rats with PAN nephrosis. Northern blot analysis was used to determine mRNA expression. Results. Immunohistochemical staining showed that heparanase protein was localized to tubular cells in the distal convoluted tubules, thick ascending limb of the loop of Henle, and transitional cell epithelium in normal kidney. Minimal expression was noted in normal glomeruli. Western blot analysis of protein from isolated normal glomeruli showed minimal expression of the 65 kD proheparanase protein. A marked increase in the staining for heparanase was found at day 5 of the PAN nephrosis model, at approximately the time of onset of proteinuria, and at day 14. Expression was predominantly seen in podocytes. At day 5, only the 65 kD proheparanase species was identified, but at day 14, mature 58 kD heparanase also was present. Northern blot analysis of sieved glomeruli at day 14 confirmed an increase in heparanase mRNA. The human podocyte cell line 56/10A1 also produced both proheparanase and mature heparanase, suggesting that podocytes can activate heparanase without other cell types. Conclusion. The previously mentioned data confirm that the novel β-D-endoglycosidase heparanase is up-regulated and activated in glomeruli from rats with proteinuria. Heparanase may be involved, therefore, in the loss of glomerular charge seen in proteinuria. Moreover,... [ABSTRACT FROM AUTHOR]

Examines the activation of nuclear factor(NF)-kB by podocytes in the autologous phase of passive Heymann nephritis (PHN). Regulation of interleukin-1beta and matrix metalloproteinase-9; Effects of pyrrolidone dithiocarbamate (PDC) on NF-kB; Administration of PDTC to rats with PHN.