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Biomedical subjects

W F Keane

Publications and source records attributed to W F Keane.

At least 37 records · Page 2Linked to original sources
PubMed1999

Recent advances in statins and the kidney.

BACKGROUND: Experimental and clinical studies have suggested a correlation between the progression of renal disease and dyslipidemia. Indeed, apolipoprotein B-containing lipoproteins have been demonstrated to be an independent risk factor for the progression of renal disease in humans. Interventional strategies in experimental models of renal disease have clearly demonstrated a beneficial effect on renal structure and function in a variety of models of renal disease. Investigations into the mechanisms whereby reduction of lipids by lipid-lowering agents benefits renal disease have suggested that the 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitors, the so-called statin class of lipid-lowering agents, may have additional effects on the biology of inflammation that are germane to the progression of renal disease. METHODS: Both in vivo and in vitro studies that investigated secondary mechanisms of statin effects are reviewed. In addition, new studies that investigated the effects on novel cellular mechanisms are presented. RESULTS: Lipid-lowering agents appear to have biologically important effects in modulating a variety of intracellular signaling systems involved in cell proliferation, inflammatory responses that involve macrophage adhesion, recruitment, and maturation. In addition, the effects on fibrogenesis have been recently defined. These latter effects may influence not only the development of glomerulosclerosis, but also interstitial fibrosis. These potentially major effects of lipid-lowering agents appear to be related to the effects on intracellular synthesis of nonsterol isoprenoids, which are involved in prenylation of critical small molecular weight proteins involved in cell signal transduction. CONCLUSIONS: In addition to the beneficial effects of the reduction in serum lipids, statins and other lipid-lowering agents may influence important intracellular pathways that are involved in the inflammatory and fibrogenic responses, which are common components of many forms of progressive renal injury.

Animals↗
PubMed1999

The central role of nuclear factor-kappa B in mesangial cell activation.

BACKGROUND: Nuclear factor-kappa B (NF-kappa B) is a family of transcription factors that is recognized by the kappa B enhancer element. Numerous proinflammatory genes have binding sites for NF-kappa B, and the products of these genes are an integral part of cellular activation and inflammatory response systems. Because there is a close relationship between NF-kappa B and mediators of cell activation, it is possible that a disruption of NF-kappa B-activating pathways may effectively influence mesangial cell activation. METHODS: We reviewed available studies related to both NF-kappa B and mesangial cells in order to provide evidence for the role of NF-kappa B in mesangial cell activation. RESULTS: Studies reported by this laboratory and others showed that various experimental maneuvers that modulate NF-kappa B activation result in a parallel modulation of proinflammatory molecule production in cultured mesangial cells. Likewise, the ability of the inhibitors of NF-kappa B activation to down-regulate the inflammatory response in animal models of renal disease has been recently demonstrated. CONCLUSIONS: These data suggest a pivotal role of NF-kappa B in mesangial cell activation and designate it as an obvious target for the modulation of this activation. Studies are necessary to characterize the role of NF-kappa B in human renal injury.

Animals↗
PubMed1999

Effects of lovastatin on expression of cell cycle regulatory proteins in vascular smooth muscle cells.

BACKGROUND: The sequential appearance of cyclins D and E is thought to initiate subsequent DNA synthesis in proliferating cells. Previous studies have reported that DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs) was suppressed by the HMG-CoA reductase inhibitor lovastatin. The effects of lovastatin on cell cycle regulatory proteins in proliferating VSMCs, however, are largely unknown. Thus, we investigated the sequential expression of cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 4, CDK2, and p27Kip1 in cultured rat VSMCs stimulated by platelet-derived growth factor (PDGF)-BB in the presence or absence of lovastatin. METHODS: Quiescent VSMCs, with and without lovastatin (20 microM) pretreatment for nine hours, were stimulated by PDGF-BB (25 ng/ml). The incorporation of tritiated thymidine was done to assess DNA synthesis. VSMC lysates were obtained every 6 hours for up to 36 hours after stimulation and were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis using relevant polyclonal antibodies. Autoradiograms were analyzed using a densitometer. RESULTS: The peak expression of cyclins D1 and E occurred at 18 and 30 hours of PDGF stimulation, respectively. Concomitant expression of CDK4 and CDK2 was also observed. The expression of p27Kip1, by contrast, was reduced in association with DNA synthesis. Lovastatin suppressed DNA synthesis and reduced the expression of cyclin D1 and cyclin E, whereas p27Kip1 expression was strongly induced by lovastatin pretreatment. CDK4 and CDK2 expression was unaffected by lovastatin treatment. CONCLUSIONS: PDGF-BB induces cyclins D1 and E prior to the onset of DNA synthesis in VSMCs. Lovastatin may suppress DNA synthesis in VSMCs by inducing p27Kip1 and reducing expression of cyclins D1 and E.

Animals↗
PubMed1999

Rabeprazole: pharmacokinetics and tolerability in patients with stable, end-stage renal failure.

The authors compare the pharmacokinetic profiles, safety, and tolerability of rabeprazole, a new proton pump inhibitor (PPI), in healthy volunteers and in subjects with stable, end-stage renal failure. This single-center, open-label trial included two groups of subjects: 10 healthy males with 24-hour creatinine clearance > or = 90 mL/min/m2 and 10 males with renal failure (24-hour creatinine clearance < or = 5 mL/min/m2) receiving hemodialytic therapy. Normal subjects received a single, oral 20 mg rabeprazole dose. Those with renal failure received a 20 mg dose of rabeprazole on the day after hemodialysis and a second dose after a 2-week washout period during dialysis. Blood samples were drawn before and up to 24 hours after rabeprazole administration for determination of plasma rabeprazole concentrations by high-performance liquid chromatography. Safety and tolerability of rabeprazole were determined by reporting adverse events and comparing vital signs, ECG, physical examinations, and clinical laboratory tests before and during treatment. Comparison of pharmacokinetic results from healthy volunteers with those from subjects with renal failure indicated no clinically significant differences between groups. In addition, there were no statistically significant differences between any pharmacokinetic parameters recorded during or after hemodialysis. Rabeprazole was well tolerated by both groups. Only two drug-related adverse events were reported, and there were no significant treatment-emergent changes in vital signs or ECG. Treatment-emergent changes in hematologic and clinical chemistry parameters were observed for a few subjects in each group and generally represented only slight deviations from the normal range. These results indicate that no dosage adjustment of rabeprazole is required in patients with renal dysfunction. These findings and the well-documented clinical efficacy of this new PPI in patients with gastric ulcers, duodenal ulcers, or gastroesophageal reflux disease support rabeprazole's use in the treatment of patients with acid peptic disorders.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1999

Importance of geranylgeranyl pyrophosphate for mesangial cell DNA synthesis.

BACKGROUND: Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are isoprenoid products of the intracellular mevalonate pathway used for prenylation of several low molecular weight G proteins, including Ras. It is likely that platelet-derived growth factor (PDGF) stimulation of mesangial cell proliferation requires prenylated, low molecular weight G proteins. The purpose of this study was to investigate the dependence of platelet-derived growth factor-stimulated mesangial cell DNA synthesis and cell membrane Ras incorporation on FPP and GGPP. METHODS: Quiescent human mesangial cells were exposed to PDGF (25 ng/ml) to stimulate DNA synthesis. Some cells were also treated with the HMG-CoA reductase inhibitor lovastatin (2.5 to 10.0 microM), which inhibits isoprenoid synthesis, in the presence or absence of exogenous FPP or GGPP. DNA synthesis was assessed by thymidine incorporation, and Western blot analysis was used to measure total cell membrane Ras. RESULTS: Stimulation of mesangial cells with PDGF did not increase total cell membrane Ras. Lovastatin reduced cell membrane Ras, and this was prevented by simultaneous exposure of mesangial cells to exogenous FPP (2.5 to 10.0 microM) or GGPP (1 to 5 microM). Lovastatin also reduced PDGF-stimulated mesangial cell DNA synthesis by 90%, and this was completely prevented by simultaneous exposure of cells to exogenous GGPP (1 microM), but not to FPP. CONCLUSIONS: The results of this study suggest that both FPP and GGPP can provide for mesangial cell membrane Ras localization and that PDGF-stimulated mesangial cell DNA synthesis requires the isoprenoid GGPP.

Blotting, Western↗
PubMed1999

Lipophilic statins induce apoptosis of human vascular smooth muscle cells.

BACKGROUND: The accumulation of vascular smooth muscle cells (VSMC) in the intima is an early feature of atherosclerosis that results from a balance of migration from the media, proliferation, and eventual death (including programmed cell death) of VSMC. Several reports have described that HMG-CoA reductase inhibitors (statins) attenuate both the migration and proliferation of VSMC. However, the potential effect of statins on VSMC programmed cell death has received little attention. METHODS: Human and rat VSMC were incubated with different concentration of statins in the presence of fetal bovine serum as a survival factor. The presence of apoptosis was evaluated by morphological criteria, flow cytometry and DNA electrophoresis. RESULTS: Lipophilic statins induced, in a dose-dependent manner the appearance of VSMC apoptosis. The effect of statins was fully reversed by mevalonate, farnesylpyrophosphate, and geranylgeranypyrophosphate, but not by cholesterol or other mevalonate metabolites, suggesting a role for isoprenoids in VSMC apoptosis. In addition, the induction of apoptosis by statins was associated with the inhibition of prenylation of Rho B. CONCLUSIONS: The present results suggest that protein prenylation inhibition by statins may be involved in statin-induced VSMC apoptosis. These data provide a new potential mechanism by which statins may modulate the evolution of atherosclerotic lesions.

Animals↗
PubMed1998

Renal cell cytokine production stimulates HIV-1 expression in chronically HIV-1-infected monocytes.

Renal infiltration of human immunodeficiency virus type 1 (HIV-1)-infected monocytes might play an important role in the development of HIV-associated nephropathy (HIVAN). In the present study, we investigated the effects of cytokines produced by cultured human mesangial cells (HMC) and proximal tubular epithelial cells (PTEC) on HIV-1 expression in chronically HIV-1-infected promonocytes (U1 cells). Human mesangial cells constitutively secreted interleukin-6 (IL-6) but not tumor necrosis factor-alpha (TNF-alpha) into the culture medium, whereas PTEC constitutively secreted both IL-6 and TNF-alpha. Coculture of U1 cells with HMC or PTEC for 72 hours markedly stimulated HIV-1 expression, with the p24 antigen concentration in the coculture supernatants ranging from approximately 200 to 1850 pg/ml. The presence of anti-IL-6 antibody in the coculture medium nearly completely blocked HIV-1 expression in the HMC/U1 cell cocultures (P < 0.05). Anti-IL-6 antibody and anti-TNF-alpha antibody blocked HIV-1 expression in the PTEC/U1 cell cocultures by 40% and 53%, respectively (P < 0.05). Moreover, the combination of anti-IL-6 and anti-TNF-alpha antibodies additively reduced coculture HIV-1 expression by 87% (P < 0.05). We conclude that renal cell production of IL-6 and TNF-alpha might provide a potent stimulus for HIV-1 expression in HIV-1-infected monocytes that infiltrate the kidney, and that this may play an important role in the pathogenesis of HIVAN.

AIDS-Associated Nephropathy↗
PubMed1998

Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats.

Glomerular expression of monocyte chemoattractant protein-1 (MCP-1) and subsequent glomerular macrophage infiltration may play an important role in the development of glomerulosclerosis. Previous studies have shown that lovastatin ameliorates experimental renal disease and reduces MCP-1 expression in serum-stimulated, cultured mesangial cells. We investigated the effects of lovastatin on glomerular MCP-1 expression and macrophage infiltration in rats with puromycin aminonucleoside (PA) nephrosis, an experimental model of renal disease characterized by early macrophage infiltration. Male Sprague-Dawley rats were pretreated for 5 days with either lovastatin (4 mg/kg) or vehicle. At the end of pretreatment, the lovastatin-pretreated rats received a single i.v. injection of PA (50 mg/kg) and continued to receive daily lovastatin thereafter. The vehicle-pretreated rats received i.v. injections of either PA or saline, and continued to receive daily vehicle treatment thereafter. Ten days after PA injection, the vehicle-treated PA rats showed increased (P < 0.05) serum cholesterol (359 +/- 25 mg/100 mL) and urine albumin excretion (343 +/- 95 mg/24 hr), compared with the vehicle-treated control rats (61 +/- 3 mg/100 mL and 2.5 +/- 0.6 mg/24 hr, respectively). Serum cholesterol (193 +/- 22 mg/dL) and urine albumin excretion (255 +/- 68 mg/24 hr) were less in the lovastatin-treated PA rats than in the vehicle-treated PA rats. The number of glomerular macrophages, assessed as ED-1-positive cells, per glomerular profile was increased 77% in the vehicle-treated PA rats (3.3 +/- 0.2) compared with the vehicle-treated control rats (1.8 +/- 0.2) (P < 0.05). By contrast, the number of glomerular macrophages was not elevated in the lovastatin-treated PA rats (2.3 +/- 0.2). Thus, lovastatin in vivo can attenuate glomerular macrophage infiltration. This may represent one mechanism by which lovastatin ameliorates experimental glomerular disease.

Animals↗
PubMed1997

Pharmacokinetics of zileuton and its metabolites in patients with renal impairment.

The pharmacokinetics of zileuton and its conjugated metabolites were evaluated in patients with chronic renal impairment. Five healthy volunteers (creatinine clearance > 90 mL/min), five patients with renal failure requiring hemodialysis, six with mild (creatinine clearance, 60-90 mL/min), eight with moderate (creatinine clearance, 30-59 mL/min), and six with severe (creatinine clearance < 30 mL/min) renal impairment participated in the study. Zileuton was well tolerated by all participants including those with severe renal impairment and those receiving hemodialysis. The pharmacokinetics of zileuton were similar in healthy volunteers; in patients with mild, moderate and severe renal impairment; and in patients with renal failure requiring hemodialysis. The mean metabolite/parent-area ratios for the pharmacologically inactive zileuton glucuronides progressively increased with the decline in renal function. A very small percentage of the administered zileuton dose (< 0.5%) was removed by hemodialysis. Therefore, adjustment in the dose regimen of zileuton does not appear to be necessary for patients with various degrees of renal impairment and patients with renal failure requiring hemodialysis.

Adult↗
PubMed1997

The long-term tolerability of enalapril in hypertensive patients with renal impairment.

There has been some concern raised regarding the safe use of ACE-inhibitors in patients with severe renal insufficiency, including the development of hyperkalaemia in these patients. Therefore, the objective of the current analysis was to evaluate the long-term safety of enalapril in patients with severe renal sufficiency and hypertension. Three protocols with similar randomized, double blind, placebo-controlled designs were selected for analysis. A total of 153 patients, enrolled at six sites, were treated for up to 3 years with enalapril; 164 patients served as controls. One protocol used a fixed dose (5 mg/day) of enalapril, while the other two protocols allowed open titration up to 40 mg/day. The primary comparison was between the enalapril and control populations. For the analysis, patients, by treatment, were grouped according to the degree of renal insufficiency (serum creatinine > or < 3 mg/dl) at baseline. The incidence of the most common, as well as important, clinical and laboratory adverse events for this patient population were summarized. In addition, trends in important laboratory adverse events and the incidence of first-dose events, cough and angioedema were evaluated. The incidence of clinical adverse events was similar for both treatment groups, regardless of the severity of renal insufficiency. Seven patients died, four in the control group and three in the enalapril treatment group; none was considered related to treatment. Enalapril appeared to be well-tolerated in this group of patients with severe renal impairment.

Adult↗
PubMed1997

Lipids in progression of renal disease.

There is increasing evidence for the role of hyperlipidemia as a contributing factor to the progression of chronic renal disease. Experimental studies in animal models suggest that lipids might be important modulators in progressive renal disease. On one hand maneuvers designed to elevate cholesterol worsen renal disease while reduction of lipid-lowering agents have demonstrated beneficial effects. In humans, correcting abnormalities in lipid metabolism with antilipemic therapy may help slow the rate of functional decline in patients with progressive renal disease as well as reduce the frequency of acute rejection after renal transplantation. However, large controlled clinical trials examining the effect of lipid-lowering strategies on progression of renal disease have not been carried out. Further clinical trials delineating the precise role of antilipemic agents in treating patients with renal disease appears warranted.

Animals↗
PubMed1997

Derangement of lipid metabolism and its management in renal transplant patients.

Hyperlipidemia is a common clinical finding in postrenal transplant patients. Increasing clinical data suggest that the dyslipidemia seen in these patients is associated with the development of atherosclerotic cardiovascular disease. In addition, recent data suggest that disordered lipid metabolism may be a risk factor for chronic allograft loss. The precise mechanisms whereby dyslipidemia contributes to vascular injury are unknown. No long-term interventional studies of lipid-lowering therapies have been conducted in this patient population. However, a number of short-term studies have shown that the newer antilipemic agents can be safely used in renal transplant patients. Thus, it appears that antilipemic therapy is warranted in renal transplant patients with an atherogenic lipid profile and multiple risk factors.

Humans↗
PubMed1997

Proteinuria is a risk factor for mortality over 10 years of follow-up. MRFIT Research Group. Multiple Risk Factor Intervention Trial.

Proteinuria has been shown to be strongly associated with the prevalence and incidence of cardiovascular disease. It has been difficult to determine if the link is causal and independent. The mortality follow-up for the Multiple Risk Factor Intervention Trial (MRFIT) randomized cohort provides an opportunity to examine these relationships. Between 1973 and 1975, 361,662 men, ages 35 to 57, were screened for blood pressure, serum cholesterol, and cigarette smoking. Patients receiving medication for diabetes were excluded. Men in the upper 10 to 15% of coronary heart disease (CHD) risk (12,866) were randomized into the MRFIT trial. Standard casual urine dipstick determinations (Labstix) for protein were done at baseline and annually for six years. Post-trial cause-specific mortality was ascertained using the National Death Index. During the trial, 2326 (18.1%) of participants had + or higher proteinuria, and 593 (4.6%) had +2 or higher proteinuria. The presence of proteinuria during the six years of follow-up was consistently associated with higher all cause, cardiovascular disease (CVD) and CHD mortality, even after adjusting for other risk factors. The higher and more persistent the proteinuria, the greater the risk. In this data set, proteinuria is a strong and independent risk factor for CVD mortality.

Cardiovascular Diseases↗