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 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 after 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-beta (TGF-beta) mRNA expression was decreased with TGL treatment. Glomerular macrophages, present in CONT and TRX rats, did not express PPAR gamma, in contrast to PPAR gamma + macrophages in control carotid artery plaque. PPAR gamma was expressed in resident cells.
Conclusions: Our results demonstrate in vivo that the PPAR gamma ligand TGL ameliorates the progression of glomerulosclerosis in a nondiabetic model. Macrophages show phenotypic diversity 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.