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Titolo:
Peroxisome proliferator-activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats
Autore:
Ma, LJ; Marcantoni, C; Linton, MF; Fazio, S; Fogo, AB;
Indirizzi:
Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 pt Pathol, Nashville, TN 37232 USA Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 Dept Med, Nashville, TN 37232 USA
Titolo Testata:
KIDNEY INTERNATIONAL
fascicolo: 5, volume: 59, anno: 2001,
pagine: 1899 - 1910
SICI:
0085-2538(200105)59:5<1899:PPRATP>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
LOW-DENSITY-LIPOPROTEIN; CHRONIC-RENAL-FAILURE; INHIBITOR TYPE-1 EXPRESSION; ANTIDIABETIC AGENT CS-045; ZUCKER FATTY RATS; PPAR-GAMMA; INSULIN-RESISTANCE; IN-VIVO; ANGIOTENSIN INHIBITION; CELL-PROLIFERATION;
Keywords:
cell turnover; plasminogen activator inhibitor-1; macrophage; p21; p27;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
78
Recensione:
Indirizzi per estratti:
Indirizzo: Fogo, AB Vanderbilt Univ, Med Ctr, Dept Pathol, MCN C3310,21st & Garland Ave, Nashville, TN 37232 USA Vanderbilt Univ MCN C3310,21st & Garland Ave Nashville TN USA 37232
Citazione:
L.J. Ma et al., "Peroxisome proliferator-activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats", KIDNEY INT, 59(5), 2001, pp. 1899-1910

Abstract

Background. Peroxisome proliferator-activated receptor-gamma (PPAR gamma) 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 PPAR gamma 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 weretreated for 12 weeks as follows: control (CONT), no further treatment; triple antihypertensive therapy (TRX); and TGL or TGL + TRX. Functional, morphological, and molecular analyses wale 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 serumcholesterol levels in TRX group. TGL groups had reduced proteinuria, serumcreatinine, and glomerulosclerosis versus CONT, in contrast to no significant effect with TRX alone (sclerosis index, 0 to 4+ scale: CONT 1.99 <plus/minus> 0.42, TGL 0.85 +/- 0.12, TGL + TRX 0.56 +/- 0.14, TRX 1.30 +/-. 0.21; TGL, P < 0.05; TGL + TRS, P = 0.01 vs. CONT). Glomerular cell proliferation, assessed by proliferating cell nuclear antigen (PCNA), was decreased after treatment with TGL ol TGL + TRX, in parallel with decreases in glomerular p21 mRNA and p27 protein compared with CENT and TRX (PCNA + cells/ glomerulus: CONT 2.04 <plus/minus> 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 decreasedin 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-p (TGF-P) mRNA expression was decreased with TGL treatment. Glomerular macrophages, present in CONT and TRX rats, did not express PPAR<gamma>, in contrast to PPARy + macrophages in control carotid artery plaque. PPAR gamma was expressed in residentcells. Conclusions. Our results demonstrate in vivo that the PPAR gamma ligand TGL ameliorates the progression of glomerulosclerosis in a nondiabetic model. Macrophages show phenotypic jiver sity in glomerular versus vascular sclerosis, with macrophage PPAR gamma expression in only the latter. PPAR gamma beneficial effects are independent of insulin/glucose effects and are associated with regulation of glomerular cell proliferation, hypertrophy, and decreased PAI-1 and TGF-beta expression.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/11/20 alle ore 16:08:51