The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent nuclear receptor that has been implicated in the modulation of critical aspects of development and homeostasis, including adipocyte differentiation, glucose metabolism and macrophage development and function. PPAR-gamma is activated by a range of synthetic and naturally occurring substances, including antidiabetic thiazolidinediones, polyunsaturated fatty acids, 15-deoxy-delta prostaglandin J2 and components of oxidized low-density lipoprotein, such as 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE). However, the identities of endogenous ligands for PPAR-gamma and their means of production in vivo have not been established. In monocytes and macrophages, 13-HODE and 15-HETE can be generated from linoleic and arachidonic acids, respectively, by a 12/15-lipoxygenase that is upregulated by the TH2-derived cytokine interleukin-4. Here we show that interleukin-4 also induces the expression of PPAR-gamma and provide evidence that the coordinate induction of PPAR-gamma and 12/15-lipoxygenase mediates interleukin-4-dependent transcription of the CD36 gene in macrophages. These findings reveal a physiological role of 12/15-lipoxygenase in the generation of endogenous ligands for PPAR-gamma, and suggest a paradigm for the regulation of nuclear receptor function by cytokines.

The peroxisome proliferator-activated receptor ␥ (PPAR␥) is a ligand-dependent transcription factor that has been demonstrated to regulate fat cell development and glucose homeostasis. PPAR␥ is also expressed in a subset of macrophages and negatively regulates the expression of several proinf lammatory genes in response to natural and synthetic ligands. We here demonstrate that PPAR␥ is expressed in macrophage foam cells of human atherosclerotic lesions, in a pattern that is highly correlated with that of oxidationspecific epitopes. Oxidized low density lipoprotein (oxLDL) and macrophage colony-stimulating factor, which are known to be present in atherosclerotic lesions, stimulated PPAR␥ expression in primary macrophages and monocytic cell lines. PPAR␥ mRNA expression was also induced in primary macrophages and THP-1 monocytic leukemia cells by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Inhibition of protein kinase C blocked the induction of PPAR␥ expression by TPA, but not by oxLDL, suggesting that more than one signaling pathway regulates PPAR␥ expression in macrophages. TPA induced the expression of PPAR␥ in RAW 264.7 macrophages by increasing transcription from the PPAR␥1 and PPAR␥3 promoters. In concert, these observations provide insights into the regulation of PPAR␥ expression in activated macrophages and raise the possibility that PPAR␥ ligands may inf luence the progression of atherosclerosis.

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Hyperglycemia is of central importance in the pathogenesis of the complications of diabetes mellitus. Glucose activation of the polyol pathway may lead to renal arteriolar smooth muscle and glomerular mesangial cell hypocontractility. In the streptozotocin-induced diabetic rat, the effect of the aldose reductase inhibitor, tolrestat, in preventing glomerular hyperfiltration, renal hypertrophy, extracellular matrix accumulation, and mesangial cell hypocontractility was addressed. Streptozotocin-induced diabetic rats were followed for 12 weeks and half received tolrestat (25 mg/kg per day). Increased glomerular filtration rate was prevented by tolrestat (3.1 +/- 0.3 vs. 1.8 +/- 0.2 mL/min, diabetes vs. diabetes + tolrestat, p < 0.01), in part by reduction of the filtration fraction (0.39 +/- 0.03 vs. 0.29 +/- 0.01, diabetes vs. diabetes + tolrestat, p < 0.01). Tolrestat prevented the raised albumin excretion rates (3594 +/- 1154 vs. 713 +/- 161 mg/24 h, diabetes vs. diabetes + tolrestat, p < 0.01). Endothelin-1-induced contraction of isolated glomeruli was normal in tolrestat-treated diabetic animals compared with the hypocontractile diabetic glomeruli. Tolrestat prevented glomerular hypertrophy (1.86 +/- 0.10 vs. 1.49 +/- 0.03 microns 2 x 10(5), diabetes vs. diabetes + tolrestat, p < 0.001) and attenuated the accumulation of basement-membrane-like material (50.2 +/- 0.4% vs. 46.4 +/- 0.8%, diabetes vs. diabetes+tolrestat, p < 0.001). Fractional mesangial expansion was unchanged in tolrestat-treated diabetic rats compared with untreated animals. Tolrestat prevents the functional changes of glomerular hyperfiltration, mesangial cell hypocontractility, and increased glomerular permeability to albumin. Polyol accumulation may have differential effects on glomerular growth and extracellular matrix accumulation in early diabetic nephropathy.