Peroxisome proliferator-activated receptor-γ agonist troglitazone protects against nondiabetic glomerulosclerosis in rats

L. J. Ma, C. Marcantoni, M. F. Linton, S. Fazio, A. B. Fogo

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    Abstract

    Background. Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily of ligand-dependent transcriptional factors with beneficial effects in diabetes mediated by improved insulin sensitivity and lipid metabolism, but potential adverse effects in atherosclerosis by promoting in vitro foam cell formation. We explored whether a PPARγ agonist, troglitazone (TGL), affects sclerosis by mechanisms unrelated to insulin and lipid effects in a model of nondiabetic glomerulosclerosis. Methods. Adult male Sprague Dawley rats underwent 5/6 nephrectomy and were treated for 12 weeks as follows: Control (CONT), no further treatment; triple antihypertensive therapy (TRX); and TGL or TGL + TRX, Functional, morphological, and molecular analyses were performed, Results. Systolic blood pressure (SBP) was increased in CONT and TGL groups (161 ± 1 and 160 ± 3 mm Hg), but not in TGL + TRX and TRX (120 ± 3 vs. 126 ± 1 mm Hg, P < 0,0001 vs. non-TRX). Serum triglyceride and cholesterol levels in all groups remained normal except for slightly higher serum cholesterol levels in TRX group. TGL groups had reduced proteinuria, serum creatinine, and glomerulosclerosis versus CONT, in contrast to no significant effect with TRX alone (sclerosis index, 0 to 4+ scale: CONT 1.99 ± 0.42, TGL 0.85 ± 0.12, TGL + TRX 0.56 ± 0.14, TRX 1.30 ± 0.21; TGL, P < 0.05; TGL + TRX, P = 0.01 vs. CONT). Glomerular cell proliferation, assessed by proliferating cell nuclear antigen (PCNA), was decreased alter treatment with TGL or TGL + TRX, in parallel with decreases in glomerular p21 mRNA and p27 protein compared with CONT and TRX (PCNA + cells/glomerulus: CONT 2.04 ± 0.64, TGL 0.84 ± 0.21, TGL + TRX 0.30 ± 0.07, TRX 1.38 ± 0.37; TGL, P < 0.05, TGL + TRX, P < 0.01 vs. CONT). Glomerular plasminogen activator inhibitor-1 (PAI-1) immunostaining was decreased in TGL or TGL + TRX groups (0 to 4+ scale, CONT 2.42 ± 0.32, TGL 1.40 ± 0.24, TGL + TRX 1.24 ± 0.17, TRX 2.53 ± 0.24; TGL or TGL + TRX vs. CONT, P < 0.05), with a parallel decrease in PAI-1 mRNA by in situ hybridization. Glomerular and tubular transforming growth factor-β (TGF-β) mRNA expression was decreased with TGL treatment, Glomerular macrophages, present in CONT and TRX rats, did not express PPARγ, in contrast to PPARγ + macrophages in control carotid artery plaque, PPARγ was expressed in resident cells. Conclusions. Our results demonstrate in vivo that the PPARγ ligand TGL ameliorates the progression of glomerulosclerosis in a nondiabetic model. Macrophages show phenotypic diversity in glomerular versus vascular sclerosis, with macrophage PPARγ expression in only the latter. PPARγ beneficial effects are independent of insulin/glucose effects and are associated with regulation of glomerular cell proliferation, hypertrophy, and decreased PAI-1 and TGF-β expression.

    Original languageEnglish (US)
    Pages (from-to)1899-1910
    Number of pages12
    JournalKidney International
    Volume59
    Issue number5
    DOIs
    StatePublished - Jan 1 2001

    Keywords

    • Cell turnover
    • Macrophage
    • Plasminogen activator inhibitor-1
    • p21
    • p27

    ASJC Scopus subject areas

    • Nephrology

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