[1503] Angiotensin II Type I Receptor Blocker Is Limited in Protection Against Severe Podocyte Injury-Induced FSGS.

Hai-Chun Yang, Shu-Wei Wang, Ira Pastan, Taiji Matsusaka, Iekuni Ichikawa, Agnes B Fogo. Vanderbilt University Medical Center, Nashville, TN; National Cancer Instiute, National Instiute of Health, Bethesda, MD; Tokai University Medical School, Isehara, Kanagawa, Japan

Background: In 5/6 Nx models in both rats and mice, we found high dose angiotensin II type I receptor blocker (ARB) prevented glomerulosclerosis progression and even could induce regression. Nep25 mice, which express the human CD25 receptor on podocytes, can dose-dependently develop progressive glomerulosclerosis when immunotoxin (LMB2) is administered and binds this receptor. Previously we have shown that renal collagen I expression was parallel to luciferin imaging in double transgenic Nep25/collagen I-luciferase mice with glomerulosclerosis induced by this toxin. In this study, we aimed to examine if ARB could protect in this model of severe primary podocyte injury-associated FSGS.
Design: Collagen I-luciferase/Nep 25 mice were exposed to a mean dose of LMB2 toxin (12.5 ng/g BW, i.p.). Mice were biopsied at week 2, randomly assigned to the ARB losartan (200mg/L) or not treated (control group), then sacrificed at week 6. Podocyte number, urine total protein/creatinine ratio, glomerulosclerosis index (SI, 0-4 scale) and collagen I associated luciferase activity were measured.
Results: LMB2 reduced podocyte number about 40% assessed by WT-1 staining (normal 7.50±0.50 vs. LMB2 4.64±0.11 /glomerulus). The control group showed edema and persistent proteinuria (week 2 66.06±14.51, week 4 72.52±11.40, week 6 87.33±29.57). Progressive glomerulosclerosis (SI, week 2 1.26±0.11 vs. week 6 1.81±0.04, p<0.05) and increased collagen I activity also developed (luciferase imaging score, week 2 0.84±0.13, week 4 1.66±0.09, week 6 1.79±0.001 ×e6, p<0.05 overtime) in control toxin-treated mice. Losartan stabilized collagen I activity (luciferase imaging score, week 2 0.96±0.18, week 4 0.78±0.10, week 6 1.06±0.13 ×e6). However, ARB did not decrease proteinuria (week 2 96.18±16.53, week 4 94.10±11.96, week 6 73.76±7.92, pNS) and did not prevent glomerulosclerosis progression (SI, week 2 1.48±0.15 vs. week 6 2.09±0.19, p<0.05).
Conclusions: Our data indicate that severe podocyte loss causes progressive glomerulosclerosis, and ARB alone cannot prevent glomerulosclerosis progression in this setting. This may be related to continuing podocyte loss cycle which accelerates the progression process.
Category: Kidney (does not include tumors)

Wednesday, March 2, 2011 1:00 PM

Poster Session VI # 237, Wednesday Afternoon

 

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