FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2024576464> ?p ?o ?g. }

• W2024576464 endingPage "463" @default.
• W2024576464 startingPage "457" @default.
• W2024576464 abstract "In addition to cholesterol lowering, 3-hydroxy-3-nethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors limit inflammatory changes associated with atherosclerosis. There is also support for their use as inhibitors of progression in chronic renal disease, irrespective of cause. In this study, their capacity to limit acute renal inflammation was evaluated. For this purpose, mice were treated with Simvastatin either prior to, at the time of, or shortly after induction of nephrotoxic nephritis. The severity of disease was determined by evaluation of blood urea nitrogen (BUN), proteinuria, and renal histologic changes. The reversibility of benefit was evaluated by the administration of mevalonic acid along with nephrotoxic serum (NTS) and Simvastatin The severity of the acute nephritis, including proteinuria, elevated BUN, and histologic changes, was ameliorated in a dose-dependent manner, when Simvastatin was administered either prior to NTS injection or at the time of NTS injection. By contrast, Simvastatin did not alter the course of established nephritis. Coadministration of mevalonic acid, the immediate substrate following HMG-CoA reductase, abolished Simvastatin's renoprotective effect, indicating that the benefit is, at least in part, due to interference with HMG-CoA reductase and biosynthetic substrates downstream from the enzyme. These findings provide the rationale for the evaluation of the efficacy of HMG-CoA reductase inhibitors in patients with recurrent forms of renal inflammation, to limit the severity of acute exacerbations of disease, prevent renal scarring and slow the rate of progression. In addition to cholesterol lowering, 3-hydroxy-3-nethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors limit inflammatory changes associated with atherosclerosis. There is also support for their use as inhibitors of progression in chronic renal disease, irrespective of cause. In this study, their capacity to limit acute renal inflammation was evaluated. For this purpose, mice were treated with Simvastatin either prior to, at the time of, or shortly after induction of nephrotoxic nephritis. The severity of disease was determined by evaluation of blood urea nitrogen (BUN), proteinuria, and renal histologic changes. The reversibility of benefit was evaluated by the administration of mevalonic acid along with nephrotoxic serum (NTS) and Simvastatin The severity of the acute nephritis, including proteinuria, elevated BUN, and histologic changes, was ameliorated in a dose-dependent manner, when Simvastatin was administered either prior to NTS injection or at the time of NTS injection. By contrast, Simvastatin did not alter the course of established nephritis. Coadministration of mevalonic acid, the immediate substrate following HMG-CoA reductase, abolished Simvastatin's renoprotective effect, indicating that the benefit is, at least in part, due to interference with HMG-CoA reductase and biosynthetic substrates downstream from the enzyme. These findings provide the rationale for the evaluation of the efficacy of HMG-CoA reductase inhibitors in patients with recurrent forms of renal inflammation, to limit the severity of acute exacerbations of disease, prevent renal scarring and slow the rate of progression. Many immune-mediated forms of glomerulonephritis are characterized by recurrent episodes of acute inflammation. With time these conditions often lead to progressive fibrosis and chronic renal failure. The efficacy of treatment with intermittent immunosuppression for disease flares is limited by timely recognition of disease activity, and severe interstitial inflammation has often occurred by the time treatment is initiated, worsening fibrosis. Continuous prophylactic immunosuppressive and/or anti-inflammatory therapy to prevent disease flares is often impractical due to substantial side effects, and disease-specific agents are currently unavailable. Treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are effective in slowing the rate of progression to renal failure in general; however, their major effects are neither anti-inflammatory nor immunosuppressive.1.Wilmer W.A. Rovin B.H. Hebert C.J. et al.Management of glomerular proteinuria: a commentary.J Am Soc Nephrol. 2003; 14: 3217-3232Crossref PubMed Scopus (184) Google Scholar In clinical practice, 3-hydroxy-3-nethylglutaryl coenzyme A (HMG-CoA) reductase-inhibiting drugs (statins) are extremely useful cholesterol-lowering agents. Inhibition of HMG-CoA reductase leads to a reduced synthesis of mevalonate. Downstream from mevalonate, the statins have three main effects: (1) reduced synthesis of cholesterol and isoprenoids, (2) reduced synthesis of farnesyl-diphospate and farnesylation of Ras family proteins, and (3) reduced geranylgeranylation of Rho family proteins. The reduced production of Ras and Rho family proteins, small membrane-bound GTPases, causes inhibition of downstream signal transduction pathways leading to suppression of the immune response by limiting T-cell maturation and activation.2.Cantrell D.A. GTPases and T cell activation.Immunol Rev. 2003; 192: 122-130Crossref PubMed Scopus (126) Google Scholar Inhibition of macrophage recruitment and function due to reduced expression of proinflammatory mediators and cytokines (e.g. nuclear factor-κB, monocyte chemoattractant protein-1, and various interleukins) has also been reported,3.Gueler F. Rong S. Park J.K. et al.Postischemic acute renal failure is reduced by short-term statin treatment in a rat model.J Am Soc Nephrol. 2002; 13: 2288-2298Crossref PubMed Scopus (127) Google Scholar, 4.Harris K.P. Purkerson M.L. Yates J. et al.Lovastatin ameliorates the development of glomerulosclerosis and uremia in experimental nephrotic syndrome.Am J Kidney Dis. 1990; 15: 16-23Abstract Full Text PDF PubMed Scopus (155) Google Scholar, 5.Koh K.K. Son J.W. Ahn J.Y. et al.Comparative effects of diet and statin on NO bioactivity and matrix metalloproteinases in hypercholesterolemic patients with coronary artery disease.Arterioscler Thromb Vasc Biol. 2002; 22: e19-e23Crossref PubMed Google Scholar, 6.Ortego M. Hernandez A.G. Bustos C. et al.3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase the binding activity and nuclear level of Oct-1 in mononuclear cells.Eur J Pharmacol. 2002; 448: 113-121Crossref PubMed Scopus (12) Google Scholar, 7.Park Y.S. Guijarro C. Kim Y. et al.Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats.Am J Kidney Dis. 1998; 31: 190-194Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 8.Sukhova G.K. Williams J.K. Libby P. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol.Arterioscler Thromb Vasc Biol. 2002; 22: 1452-1458Crossref PubMed Scopus (219) Google Scholar, 9.Yokota N. O'Donnell M. Daniels F. et al.Protective effect of HMG-CoA reductase inhibitor on experimental renal ischemia-reperfusion injury.Am J Nephrol. 2003; 23: 13-17Crossref PubMed Scopus (83) Google Scholar and this is likely a major contributor to efficacy. These observations provide the rationale to use statins as therapeutic agents to limit progression of inflammatory diseases such as recurrent forms of glomerulonephritis. Toward this end, we evaluated the efficacy of Simvastatin treatment in the acute phase of nephrotoxic nephritis. Injection of nephrotoxic serum (NTS) into C57BL/6 mice caused severe nephritis. These mice had heavy proteinuria, hypercholesterolemia, oliguric acute renal failure, and histological evidence of acute glomerulonephritis (Figures 1 and 2). By contrast, coadministration of Simvastatin was associated with protection against nephritis (Figures 1 and 2). The beneficial effect was most pronounced in mice that were pretreated with Simvastatin, although simultaneous administration of Simvastatin was also protective. Simvastatin treatment limited proteinuria, and it was associated with significantly less fluid retention and weight gain; by day 6 of the study, mice pretreated with Simvastatin gained only 2% weight following the NTS injection as compared to 12.5% in the simultaneously treated group and 35% in the untreated group (Figure 1a). Simvastatin-treated mice had minimal proteinuria and minimal elevations in blood urea nitrogen (BUN) (Figure 1b).Figure 2Simvastatin reduces the severity of NTS nephritis.Histology: (a): NTS injected mice with enlarged hypercellular glomeruli (arrow) and dilated renal tubules with proteinaceus fluid (arrowhead). There was also ATN in some specimens (not shown). (b) By contrast, histology was normal in mice that received simvastatin pretreatment. (c) Similarly, mice that received simvastatin with NTS had less nephritis. (d) Mevalonic acid reverses to histology of NTS nephritis. (e) Distribution of glomerular histology showing significantly reduced severity of the glomerulonephritis by histological criteria in the simvastatin-treated groups.View Large Image Figure ViewerDownload (PPT) Histologic evaluation confirmed the biochemical results and revealed no evidence of glomerulonephritis in mice treated with Simvastatin in doses greater than 10 mg/kg (Figure 2). These findings were confirmed in three separate experiments. All animals had intense staining for sheep IgG; however, there was no evidence of a mouse anti-sheep immune response, as determined by immunofluorescent staining of the kidneys (data not shown). The timing of the Simvastatin administration was crucial to its beneficial effect. When Simvastatin treatment was initiated at either 30 or 72 h after NTS administration, the mice had severe nephritis with nephrotic syndrome and acute oliguric renal failure that was indistinguishable from mice that received NTS alone (data not shown). The renoprotective benefits were dose dependent, as Simvastatin in doses of 25 and 10 mg/kg were effective in preventing the development of NTS nephritis, while the 1 mg/kg dose was not protective (Figure 3). Nephritis in the latter group of mice was indistinguishable from the mice that received NTS alone (P>0.05). Simvastatin treatment did not effect the deposition of sheep IgG within the glomeruli, as all mice (in all groups) had strongly positive linear deposits of IgG (4+) within the glomeruli. Simvastatin treatment alone lowered BUN in control mice (P<0.01), but it did not affect s-cholesterol or cause proteinuria (Table 1).Table 1Effect of Simvastatin treatment of mice (n=5)Pre-treatmentPost-treatmentPWeight (g)21.6 (1.3)22.1 (0.8)NSS-BUN (mg/dl)37.5 (2.1)24.9 (3.08)<0.001S-cholesterol (mg/dl)72.4 (13.3)56.8 (19.5)NSHistology scoreNot doneNot done—Proteinuria (mg/day)Not doneNot done— Open table in a new tab Low serum cholesterol levels were not linked to the beneficial, renoprotective effects on nephritis, as mice that received Simvastatin and NTS simultaneously were protected from nephritis and oliguric renal failure, despite elevated serum cholesterol levels (Figure 1). This finding raised the possibility that the renoprotective anti-inflammatory benefit observed was independent from the cholesterol lowering. To more directly address this issue, independent evaluations were performed. Cholesterol lowering was compared to renoprotection, as the dose of Simvastatin was reduced. The renoprotective benefits were dose dependent, as described above. However, although Simvastatin in doses of 25 and 10 mg/kg were effective in preventing nephritis, serum cholesterol was not lowered in the mice that received the 10 mg/kg dose. The 1 mg/kg dose of Simvastatin neither lowered cholesterol nor was renoprotective. Mevalonic acid administered with Simvastatin (and NTS) completely reversed the protective effects of Simvastatin (Figures 1, 2 and 3). These mice developed severe nephritis indistinguishable from mice that received only NTS. Within this group two mice died. Mevalonic acid alone had no effect on disease, as these mice developed severe nephritis, proteinuria, and elevated BUN levels. In the present study, the effects of Simvastatin on the acute phase of NTS nephritis were evaluated. Simvastatin attenuated the effects of nephritis when administered either prior to or at the time of disease induction, although renoprotection was greatest when it was administered prior to disease onset. By contrast, Simvastatin administration after disease was established was not effective. Simvastatin reduced the degree of proteinuria, prevented elevation of BUN levels and limited the pathologic effects induced by NTS. The effect appeared to be unrelated to the quantity of sheep IgG deposited, as all of the mice had intense staining for sheep IgG. The benefit also appeared to be independent of its cholesterol lowering effect, as low serum cholesterol levels were not consistently linked to renoprotection. In this respect, the mice that received Simvastatin and NTS simultaneously were protected from nephritis, despite very high serum cholesterol levels. The renoprotection was reversed by repletion of mevalonic acid, indicating that the effect was mediated through substrates generated downstream from mevalonate (Figure 4). Elucidation of the precise pathway will require further study. Although Simvastatin has been reported to increase renal plasma flow,10.van Dijk M.A. Kamper A.M. van Veen S. et al.Effect of simvastatin on renal function in autosomal dominant polycystic kidney disease.Nephrol Dial Transplant. 2001; 16: 2152-2157Crossref PubMed Scopus (80) Google Scholar an effect shown by reduced BUN levels in the Simvastatin control group, we do not believe that this was a major contributing factor to the improved renal function with Simvastatin. In all likelihood, this contribution to glomerular filtration rate may have been offset by an increased delivery of nephrotoxic antibodies to glomeruli. Nevertheless, although clinical and pathologic evidence of nephritis was reversed by the mevalonate, these animals did not gain weight typical of the nephrotic syndrome. We suspect that decreased food and water intake in these animals was likely secondary to a direct effect of the mevalonic acid, since there was clinical (proteinuria) and histologic evidence of severe nephritis in the mice. It is generally appreciated that statins slow progression of renal scaring and limit atherosclerosis associated with chronic renal failure. These benefits have been documented both in patients and in animal models, and their efficacy is likely related to the combined effects of lipid lowering, antiatherogenic, and anti-inflammatory activities.11.Bianchi S. Bigazzi R. Caiazza A. et al.A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease.Am J Kidney Dis. 2003; 41: 565-570Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar, 12.Buemi M. Senatore M. Corica F. et al.Statins and progressive renal disease.Med Res Rev. 2002; 22: 76-84Crossref PubMed Scopus (69) Google Scholar, 13.Kim S.I. Han D.C. Lee H.B. Lovastatin inhibits transforming growth factor-beta1 expression in diabetic rat glomeruli and cultured rat mesangial cells.J Am Soc Nephrol. 2000; 11: 80-87PubMed Google Scholar, 14.O'Donnell M. Kasiske B. Kim Y. et al.Lovastatin retards the progression of established glomerular disease in obese Zucker rats.Am J Kidney Dis. 1993; 22: 83-89Abstract Full Text PDF PubMed Scopus (95) Google Scholar, 15.Vidt D.G. Cressman M.D. Harris S. et al.Rosuvastatin-induced arrest in progression of renal disease.Cardiology. 2004; 102: 52-60Crossref PubMed Scopus (151) Google Scholar Evidence that renoprotection has a cholesterol-independent component was raised by the findings of Katzav and co-workers, who observed that Ras inhibition with farnesylthiosalicylate in spontaneous murine lupus in MRL-lpr/lpr lupus mice attenuated nephritis.16.Katzav A. Kloog Y. Korczyn A.D. et al.Treatment of MRL/lpr mice, a genetic autoimmune model, with the Ras inhibitor, farnesylthiosalicylate (FTS).Clin Exp Immunol. 2001; 126: 570-577Crossref PubMed Scopus (41) Google Scholar However, distinction between immunosuppression and direct effect on the kidney was not possible, since the treatment also reduced circulating autoantibodies levels. The present study was designed to eliminate the potential confounding, immunosuppressive effects of Simvastatin on the adaptive immune response, as the dose of NTS was similar in all groups, and the study was ended prior to the usual appearance of an anti-sheep IgG response. In this regard, the mice were not preimmunized with sheep IgG to avoid the potential influence of Simvastatin on the production of mouse anti-sheep IgG antibodies, and spontaneous production of mouse anti-sheep IgG is typically not apparent until 7–10 days after the administration of sheep IgG. Both of these factors could have confounded interpretation. Evidence that statins and Ras inhibition limit acute renal injury has been reported in other experimental diseases. In the anti-thy 1 model, Clarke et al.17.Clarke H.C. Kocher H.M. Khwaja A. et al.Ras antagonist farnesylthiosalicylic acid (FTS) reduces glomerular cellular proliferation and macrophage number in rat thy-1 nephritis.J Am Soc Nephrol. 2003; 14: 848-854Crossref PubMed Scopus (31) Google Scholar observed that farnesylthiosalicylate inhibition of Ras limited the severity of nephritis. In these studies, antibody (anti-Thy 1)-mediated, complement-dependent apoptosis of mesangial cells results in proteinuria; this is typically followed by mesangial proliferation and eventual restoration of renal function. Farnesylthiosalicylate reduced both proteinuria and proliferation. Statins were also found to attenuate the reduction of glomerular filtration rate and pathologic effects of ischemia-induced renal failure in mice, limit proteinuria and macrophage infiltration in puromycin aminoglycoside-induced nephrosis, and alter the course of passive Heymann nephritis in rats. In the passive Heymann nephritis model, Simvastatin reduced the expression of monocyte chemoattractant protein-1, and the benefit was enhanced by angiotensin-converting enzyme inhibition.18.Zoja C. Corna D. Rottoli D. et al.Effect of combining ACE inhibitor and statin in severe experimental nephropathy.Kidney Int. 2002; 61: 1635-1645Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar In puromycin-induced nephrosis, Lovastatin reduced monocyte chemoattractant protein-1 and macrophage recruitment and infiltration,4.Harris K.P. Purkerson M.L. Yates J. et al.Lovastatin ameliorates the development of glomerulosclerosis and uremia in experimental nephrotic syndrome.Am J Kidney Dis. 1990; 15: 16-23Abstract Full Text PDF PubMed Scopus (155) Google Scholar, 7.Park Y.S. Guijarro C. Kim Y. et al.Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats.Am J Kidney Dis. 1998; 31: 190-194Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar whereas in the ischemia model, Lovastatin caused an increased interleukin-6 expression and dampened renal inflammation.3.Gueler F. Rong S. Park J.K. et al.Postischemic acute renal failure is reduced by short-term statin treatment in a rat model.J Am Soc Nephrol. 2002; 13: 2288-2298Crossref PubMed Scopus (127) Google Scholar, 9.Yokota N. O'Donnell M. Daniels F. et al.Protective effect of HMG-CoA reductase inhibitor on experimental renal ischemia-reperfusion injury.Am J Nephrol. 2003; 23: 13-17Crossref PubMed Scopus (83) Google Scholar Our studies extend these findings to an acute inflammatory model of antibody-mediated, glomerulonephritis, involving infiltration of polymorphonuclear cells and macrophages. Common to the benefits in all of these models is the reduction in cellular recruitment and infiltration, and it is consistent with the anti-inflammatory actions of the drug. In this regard, the acute anti-inflammatory and renoprotective effects of Simvastatin in the present study were, at least in part, independent of lipid lowering, consistent with other recent observations with HMG-CoA reductase inhibitors. Simvastatin was observed to improve survival in mice rendered septic by cecal ligation and perforation. In this model, improved cardiac function was associated with restored responsiveness to dobutamine and resistance to bradykinin-induced stimulation of endothelial nitric oxide-mediated reduction in coronary artery blood flow.19.Merx M.W. Liehn E.A. Janssens U. et al.HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis.Circulation. 2004; 109: 2560-2565Crossref PubMed Scopus (243) Google Scholar Simvastatin has also been found to inhibit leukocytic adhesion to the endothelium,20.Kimura M. Kurose I. Russell J. et al.Effects of fluvastatin on leukocyte–endothelial cell adhesion in hypercholesterolemic rats.Arterioscler Thromb Vasc Biol. 1997; 17: 1521-1526Crossref PubMed Scopus (193) Google Scholar inhibit major histocompatibility complex-II expression on macrophages, leading to altered maturation and activation of T cells.2.Cantrell D.A. GTPases and T cell activation.Immunol Rev. 2003; 192: 122-130Crossref PubMed Scopus (126) Google Scholar, 21.Kwak B. Mulhaupt F. Myit S. et al.Statins as a newly recognized type of immunomodulator.Nat Med. 2000; 6: 1399-1402Crossref PubMed Scopus (1234) Google Scholar These latter effects may contribute to improved outcome in human cardiac transplantation.22.Horimoto H. Nakai Y. Nakahara K. et al.HMG-COA reductase inhibitor cerivastatin prolonged rat cardiac allograft survival by blocking intercellular signals.J Heart Lung Transplant. 2001; 20: 227Abstract Full Text Full Text PDF PubMed Google Scholar, 23.Shimizu K. Aikawa M. Takayama K. et al.Direct anti-inflammatory mechanisms contribute to attenuation of experimental allograft arteriosclerosis by statins.Circulation. 2003; 108: 2113-2120Crossref PubMed Scopus (97) Google Scholar In the present study, although effects on antigen presentation are unlikely to be a major contributor to benefit, inhibition of cellular infiltration may be operative, as statins were found to reduce macrophage influx into inflamed tissues.7.Park Y.S. Guijarro C. Kim Y. et al.Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats.Am J Kidney Dis. 1998; 31: 190-194Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar These observations are particularly relevant to the nephrotoxic nephritis model, as both polymorphonuclear cells and macrophages infiltration are involved in the pathogenesis of the acute phase of disease. A potential mechanism is suggested by recent observations that statins inhibit Fc receptor-mediated phagocytosis by macrophages, since both macrophage infiltration and Fc receptor dependence of nephritis has been found in this model.24.Loike J.D. Shabtai D.Y. Neuhut R. et al.Statin inhibition of Fc receptor-mediated phagocytosis by macrophages is modulated by cell activation and cholesterol.Arterioscler Thromb Vasc Biol. 2004; 24: 2051-2056Crossref PubMed Scopus (53) Google Scholar Other related effects of statins may also have contributed. They have been observed to inhibit expression of acute-phase reactants, cytokines, and chemotaxic factors,3.Gueler F. Rong S. Park J.K. et al.Postischemic acute renal failure is reduced by short-term statin treatment in a rat model.J Am Soc Nephrol. 2002; 13: 2288-2298Crossref PubMed Scopus (127) Google Scholar, 5.Koh K.K. Son J.W. Ahn J.Y. et al.Comparative effects of diet and statin on NO bioactivity and matrix metalloproteinases in hypercholesterolemic patients with coronary artery disease.Arterioscler Thromb Vasc Biol. 2002; 22: e19-e23Crossref PubMed Google Scholar, 6.Ortego M. Hernandez A.G. Bustos C. et al.3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase the binding activity and nuclear level of Oct-1 in mononuclear cells.Eur J Pharmacol. 2002; 448: 113-121Crossref PubMed Scopus (12) Google Scholar, 7.Park Y.S. Guijarro C. Kim Y. et al.Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats.Am J Kidney Dis. 1998; 31: 190-194Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 8.Sukhova G.K. Williams J.K. Libby P. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol.Arterioscler Thromb Vasc Biol. 2002; 22: 1452-1458Crossref PubMed Scopus (219) Google Scholar, 9.Yokota N. O'Donnell M. Daniels F. et al.Protective effect of HMG-CoA reductase inhibitor on experimental renal ischemia-reperfusion injury.Am J Nephrol. 2003; 23: 13-17Crossref PubMed Scopus (83) Google Scholar, 14.O'Donnell M. Kasiske B. Kim Y. et al.Lovastatin retards the progression of established glomerular disease in obese Zucker rats.Am J Kidney Dis. 1993; 22: 83-89Abstract Full Text PDF PubMed Scopus (95) Google Scholar, 25.Diomede L. Albani D. Sottocorno M. et al.In vivo anti-inflammatory effect of statins is mediated by nonsterol mevalonate products.Arterioscler Thromb Vasc Biol. 2001; 21: 1327-1332Crossref PubMed Scopus (209) Google Scholar, 26.Ortego M. Bustos C. Hernandez-Presa M.A. et al.Atorvastatin reduces NF-kappaB activation and chemokine expression in vascular smooth muscle cells and mononuclear cells.Atherosclerosis. 1999; 147: 253-261Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar which could also inhibit, cellular recruitment, limit activation of monocytes, and reduce endogenous (renal) cell participation. This latter, conclusion is consistent with the findings of Zager et al.27.Zager R.A. Johnson A.C. Hanson S.Y. Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses the SR-B1 cholesterol transporter.Kidney Int. 2003; 63: 123-133Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar and Johnson et al.,28.Johnson A.C. Yabu J.M. Hanson S. et al.Experimental glomerulopathy alters renal cortical cholesterol, SR-B1, ABCA1, and HMG CoA reductase expression.Am J Pathol. 2003; 162: 283-291Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar who suggested that the renoprotection of statins in acute renal failure was due to either anti-inflammatory properties or an effect of lowering systemic lipid levels. Nevertheless, we intentionally designed the study to both eliminate the potential immunosuppressive effects of the agents and to limit the effects on renal progression, per se. Collectively, these statin-induced renoprotective effects suggest that these drugs may be beneficial in the treatment of human immune-mediated renal diseases. In addition to limiting progression of chronic renal disease, we suggest that patients suffering from recurrent episodes of acute renal inflammation, such as those with lupus nephritis or IgA nephropathy, may benefit. These patients are at risk of progressive loss of renal function due to recurring flares of acute disease. Pathologic evidence of both inflammation and fibrosis are often present at the initiation of immunosuppressive therapy or on re-biopsy, consistent with the notion that disease activity is present before initial presentation and between overt disease flares. In these patients, statins have the potential to limit disease severity during acute flares, reduce the number of flares or/and thereby limit progressive loss of renal function. Our results, therefore, provide the basis for evaluating use of these drugs in patients with recurrent forms of nephritis as a means to limit the rate of disease progression. Female C57BL/6 mice were purchased from Jackson Laboratories. All experiments were performed in mice of 8–12 weeks of age; the mice weighed 17–22 g at induction of disease. All experiments were conducted according to the NIH Guide for the Care and Use of Laboratory Animals. NTS was prepared in sheep, using mouse glomeruli, as described previously.29.Sogabe H. Nangaku M. Ishibashi Y. et al.Increased susceptibility of decay-accelerating factor deficient mice to anti-glomerular basement membrane glomerulonephritis.J Immunol. 2001; 167: 2791-2797Crossref PubMed Scopus (77) Google Scholar Alexaflour 488-labeled donkey anti-sheep IgG was purchased from Molecular Probes. Mevalonic acid was purchased from Sigma-Aldrich (MO, USA). Simvastatin was a generous gift from Merck (PA, USA). The experimental design is presented in Figure 5. Sheep NTS, 10 ml/kg, intraperitoneally, was administered as a single dose to the mice. A single lot of NTS was used for all experiments. In preliminary studies, the dose was determined so that all mice had intense (4+) linear sheep IgG deposits along the glomerular basement membrane, light microscopic evidence of nephritis, and heavy proteinuria. All mice were weighed prior to NTS dosing, at 3 and 6 days after NTS administration. Simvastatin (4 mg/ml, pH 7.4) was administered to mice in daily doses of 1, 10, or 25 mg/kg by intraperitoneal injection. Simvastatin treatment was given in four different dosing regimens: either starting on day -6 (n=15), day 0 (n=10), day +1 (n=5) or day +3 (n=5) as compared to administration of the NTS. Simvastatin alone was also given to C57BL/6 mice (n=5), to serve as controls. A cohort of mice (n=10) was given mevalonic acid (25 mg/kg) with Simvastatin and NTS. Mevalonic acid was administered by daily intraperitoneal injections. As a control, mevalonic acid was also given with NTS (n=10). Twenty-four hours urinary protein excretion was determined prior to and 6 days after NTS administration, by timed urine collection in metabolic cages, using the Bio-Rad protein assay method (Bio-Rad Laboratories, Hercules, CA). BUN levels were measured using the Stanbio enzymatic urea procedure (Stanbio Laboratory, Boerne, Texas). Serum cholesterol levels were determined using a cholesterol reagent set (Point Scientific, Lincoln Park, Michigan). At the time of killing, one of the kidneys was snap-frozen, sectioned (4 μm) and examined by direct immunofluorescence, using fluoresceinated donkey anti-sheep IgG. The other kidney was fixed in phosphate-buffered formalin, sectioned, and then stained with hematoxylin and eosin. The histological severity of the glomerulonephritis, which at this stage is mainly infiltrative, was graded (0–4+) as described previously30.Chan O. Madaio M.P. Shlomchik M.J. The roles of B cells in MRL/lpr murine lupus.Ann NY Acad Sci. 1997; 815: 75-87Crossref PubMed Scopus (50) Google Scholar by a single observer (MPM) who was blinded to the origin of the mice. Owing to the small number of mice used in each group and the presence of small interstitial infiltrates in some mice, kidneys with a histology score of 2 or less were termed ‘mild nephritis’, whereas mice with a score of 3 or more was called ‘severe nephritis’. All values are presented as means±standard deviation. Statistical analyses were performed using a nonparametric test, analysis of variance, with comparison of individual groups. When appropriate, a two-sided Student's t-test was used. A P-value less than 0.05 were taken to indicate statistical significance. This work was supported by National Institutes of Health Grants K08 DK062836 (to MC), R01 DK0523088 (to MPM), The Kidney Foundation of Central Pennsylvania (to JHL), T32-DK07006 (to AWS and RWS) and The Carol Ann Wilson Endowed Fellowship in Pediatric Nephrology, The Children's Hospital of Philadelphia (to AG)." @default.
• W2024576464 created "2016-06-24" @default.
• W2024576464 creator A5010542292 @default.
• W2024576464 creator A5025004680 @default.
• W2024576464 creator A5056567867 @default.
• W2024576464 creator A5068860176 @default.
• W2024576464 creator A5072881309 @default.
• W2024576464 creator A5089587112 @default.
• W2024576464 date "2006-02-01" @default.
• W2024576464 modified "2023-10-15" @default.
• W2024576464 title "Simvastatin protection against acute immune-mediated glomerulonephritis in mice" @default.
• W2024576464 cites W1525331105 @default.
• W2024576464 cites W1714774488 @default.
• W2024576464 cites W1963913523 @default.
• W2024576464 cites W1970612654 @default.
• W2024576464 cites W1978615396 @default.
• W2024576464 cites W1984610769 @default.
• W2024576464 cites W1996372969 @default.
• W2024576464 cites W1998747783 @default.
• W2024576464 cites W1999943358 @default.
• W2024576464 cites W2020248106 @default.
• W2024576464 cites W2038261200 @default.
• W2024576464 cites W2042469629 @default.
• W2024576464 cites W2046206902 @default.
• W2024576464 cites W2050392973 @default.
• W2024576464 cites W2069631424 @default.
• W2024576464 cites W2075474963 @default.
• W2024576464 cites W2084671094 @default.
• W2024576464 cites W2089479425 @default.
• W2024576464 cites W2099485659 @default.
• W2024576464 cites W2101649211 @default.
• W2024576464 cites W2110754607 @default.
• W2024576464 cites W2113101136 @default.
• W2024576464 cites W2121647253 @default.
• W2024576464 cites W2134275717 @default.
• W2024576464 cites W2138432239 @default.
• W2024576464 cites W2147912194 @default.
• W2024576464 cites W2161641403 @default.
• W2024576464 cites W2161821089 @default.
• W2024576464 cites W2171535344 @default.
• W2024576464 cites W4233042667 @default.
• W2024576464 doi "https://doi.org/10.1038/sj.ki.5000086" @default.
• W2024576464 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16407885" @default.
• W2024576464 hasPublicationYear "2006" @default.
• W2024576464 type Work @default.
• W2024576464 sameAs 2024576464 @default.
• W2024576464 citedByCount "29" @default.
• W2024576464 countsByYear W20245764642013 @default.
• W2024576464 countsByYear W20245764642014 @default.
• W2024576464 countsByYear W20245764642015 @default.
• W2024576464 countsByYear W20245764642016 @default.
• W2024576464 countsByYear W20245764642017 @default.
• W2024576464 countsByYear W20245764642018 @default.
• W2024576464 countsByYear W20245764642023 @default.
• W2024576464 crossrefType "journal-article" @default.
• W2024576464 hasAuthorship W2024576464A5010542292 @default.
• W2024576464 hasAuthorship W2024576464A5025004680 @default.
• W2024576464 hasAuthorship W2024576464A5056567867 @default.
• W2024576464 hasAuthorship W2024576464A5068860176 @default.
• W2024576464 hasAuthorship W2024576464A5072881309 @default.
• W2024576464 hasAuthorship W2024576464A5089587112 @default.
• W2024576464 hasBestOaLocation W20245764641 @default.
• W2024576464 hasConcept C126322002 @default.
• W2024576464 hasConcept C203014093 @default.
• W2024576464 hasConcept C2776329913 @default.
• W2024576464 hasConcept C2780091579 @default.
• W2024576464 hasConcept C2780368995 @default.
• W2024576464 hasConcept C71924100 @default.
• W2024576464 hasConcept C8891405 @default.
• W2024576464 hasConcept C98274493 @default.
• W2024576464 hasConceptScore W2024576464C126322002 @default.
• W2024576464 hasConceptScore W2024576464C203014093 @default.
• W2024576464 hasConceptScore W2024576464C2776329913 @default.
• W2024576464 hasConceptScore W2024576464C2780091579 @default.
• W2024576464 hasConceptScore W2024576464C2780368995 @default.
• W2024576464 hasConceptScore W2024576464C71924100 @default.
• W2024576464 hasConceptScore W2024576464C8891405 @default.
• W2024576464 hasConceptScore W2024576464C98274493 @default.
• W2024576464 hasIssue "3" @default.
• W2024576464 hasLocation W20245764641 @default.
• W2024576464 hasLocation W20245764642 @default.
• W2024576464 hasOpenAccess W2024576464 @default.
• W2024576464 hasPrimaryLocation W20245764641 @default.
• W2024576464 hasRelatedWork W2260183141 @default.
• W2024576464 hasRelatedWork W2359454541 @default.
• W2024576464 hasRelatedWork W2371253382 @default.
• W2024576464 hasRelatedWork W2375384524 @default.
• W2024576464 hasRelatedWork W2386926241 @default.
• W2024576464 hasRelatedWork W2388892545 @default.
• W2024576464 hasRelatedWork W4205955005 @default.
• W2024576464 hasRelatedWork W4213195014 @default.
• W2024576464 hasRelatedWork W4386740662 @default.
• W2024576464 hasRelatedWork W2141639350 @default.
• W2024576464 hasVolume "69" @default.
• W2024576464 isParatext "false" @default.
• W2024576464 isRetracted "false" @default.
• W2024576464 magId "2024576464" @default.
• W2024576464 workType "article" @default.