Volume 69, Issue 3, Pages (February 2006)

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Volume 69, Issue 3, Pages 457-463 (February 2006) Simvastatin protection against acute immune-mediated glomerulonephritis in mice M. Christensen, A.W. Su, R.W. Snyder, A. Greco, J.H. Lipschutz, M.P. Madaio Kidney International Volume 69, Issue 3, Pages 457-463 (February 2006) DOI: 10.1038/sj.ki.5000086 Copyright © 2006 International Society of Nephrology Terms and Conditions

Figure 1 Simvastatin reduces the severity of NTS nephritis. (a) Weight: Fractional weight increase during the experiment (expressed as d3/pretreatment-d1) and d6/pretreatment-d1; (b) 24 h urine protein (mg/day); (c) BUN levels (mg/dl); and (d) serum cholesterol (mg/dl). *P<0.05; **P<0.001; NS, not significantly different. ▪, pretreatment; post-treatment. Kidney International 2006 69, 457-463DOI: (10.1038/sj.ki.5000086) Copyright © 2006 International Society of Nephrology Terms and Conditions

Figure 2 Simvastatin 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. Kidney International 2006 69, 457-463DOI: (10.1038/sj.ki.5000086) Copyright © 2006 International Society of Nephrology Terms and Conditions

Figure 3 Dose-dependent renoprotection of simvastatin in NTS nephritis. (a) Weight: Fractional weight increase over the experimental period (d6/d0); (b) 24 h urine protein (mg/day); (c) BUN (mg/dl); and (d) serum cholesterol (mg/dl). Pretreatment values are compared to post-treatment values and comparisons are carried out between post-treatment values in the three group (the bars). *P<0.05; **P<0.001; NS, not significantly different. ▪, Pretreatment; , post-treatment. Kidney International 2006 69, 457-463DOI: (10.1038/sj.ki.5000086) Copyright © 2006 International Society of Nephrology Terms and Conditions

Figure 4 Biosynthesis of cholesterol and GTPases. Kidney International 2006 69, 457-463DOI: (10.1038/sj.ki.5000086) Copyright © 2006 International Society of Nephrology Terms and Conditions

Figure 5 Experimental design. Groups A: NTS only (n=10); B: NTS with prophylactic simvastatin treatment (n=15); C: simvastatin and NTS given simultaneously (n=10); D: delayed simvastatin treatment (two groups, each n=5, in one simvastatin was delayed 30 h in the other 72 h); E: NTS with simvastatin and mevalonic acid pretreatment (n=10). As controls mice in group F received mevalonic acid pretreatment, NTS but no simvastatin (n=5), and mice in group G were given simvastatin but no NTS. NTS was only given as a single injection on day 6 (n=5). Twenty-four hour urines were collected on day -1 and day 12. All mice were killed on day 13. , Daily NaCl injections; , daily simvastatin injections; and , daily mevalonic acid injections. Kidney International 2006 69, 457-463DOI: (10.1038/sj.ki.5000086) Copyright © 2006 International Society of Nephrology Terms and Conditions