Risk of coronary artery disease (CAD) is determined by a combination of genetic and environmental factors which influence plasma lipid homeostasis, haemostasis and inflammation. Peroxisome proliferator activated receptor alpha (PPARa) is a ligand-inducible transcription factor [1] which regulates the expression of genes involved in fatty acid oxidation, extracellular lipid metabolism, haemostasis [2] and inflammation [3]. Ligands for PPARa include long chain fatty acids, eicosanoids, peroxisome proliferators, non-steroidal anti-inflammatory drugs and the fibrate class of hypolipidaemic drugs [4±6]. PPARa is highly expressed in tissues with a high rate of fatty Diabetologia (2000) Methods. The human PPARa gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determined for 129 Type II diabetic subjects and 2508 healthy men. The association with plasma lipid concentrations was examined. The function of the V162 variant was examined in co-transfection assays.Results. We identified two polymorphisms, one in intron 3 and a missense mutation, leucine 162 to valine, in the DNA binding domain. In Type II diabetic patients, V162 allele carriers had higher total cholesterol, HDL cholesterol and apoAI whereas intron 3 rare allele carriers had higher apoAI concentrations. By contrast, no effect was observed in healthy rare allele carriers. In vitro, the V162 variant showed greater transactivation of a reporter gene construct. Conclusion/interpretation. Naturally occurring variation alters PPARa function, influencing plasma lipid concentrations in Type II diabetic patients but not healthy people. This demonstrates that PPARa is a link between diabetes and dyslipidaemia, and so could influence the risk of coronary artery disease, the greatest cause of morbidity and mortality in Type II diabetes. [Diabetologia (2000) 43: 673±680]

In summary, both the developing atherosclerotic and FSGS lesions seem to share certain postulated pathophysiologic mechanisms, including endothelial cell injury, macrophage infiltration, hyperlipoproteinemia, and hypertension. As depicted in Figure 1, any initial glomerular injury results in flux of macromolecular substances into the glomerular mesangium. As an adjunct to increased glomerular barrier dysfunction, hyperlipoproteinemia is believed to secondarily develop from the dramatic losses of albumin, stimulating increased hepatic lipoprotein synthesis and the loss of lipoprotein lipase-activating substance into the urine which would effectively produce a reduction in circulating chylomicra and triglyceride catabolism. Certain elevated circulating lipoproteins could, theoretically, pass through the damaged glomerular filter into the mesangium, thereby enhancing the flux of macromolecules. Also associated with certain experimental glomerular disorders is the development of glomerular hypertension, as manifested by an elevated glomerular capillary hydrostatic pressure (PGC), which can further augment macromolecular flux into the mesangium. Overloading of the glomerular mesangium by the above mechanisms is believed to be an injurious stimulus for MC to both proliferate and produce excess mesangial matrix substance. Both of these events are thought to be pathologic harbingers of glomerulosclerosis. Glomerular hypertension is also capable of damaging endothelial cells within the glomerular microcirculation, and this purportedly can activate platelets and result in glomerular thrombosis. At present, it is unclear how glomerular thrombosis produces increased mesangial cell injury; however, this process is believed to cause both systemic and glomerular hypertension which may serve as intermediary mechanisms producing the untoward effects of mesangial cell proliferation and matrix overproduction.

Early cellular and molecular derangements have been evaluated as potential pivotal factors for the late development of interstitial fibrosis after experimental hydronephrosis. In this study, we delineated the kinetics of renal cortical macrophage infiltration as well as the cortical expression of transforming growth factor-beta 1 (TGF-beta 1) and monocyte chemoattractant peptide-1 (MCP-1) at 12, 48, and 96 h after unilateral ureteral obstruction (UUO). Interstitial macrophage number in the obstructed kidney versus the contralateral unobstructed kidney (CUK) significantly increased by 12 (11.1 +/- 0.9 vs. 4.5 +/- 0.6), 48 (27.5 +/- 0.9 vs. 4.0 +/- 0.8), and 96 h (71.4 +/- 4.6 vs. 3.2 +/- 0.4) after UUO. MCP-1 mRNA was detected from 12 to 96 h in the obstructed kidney but was absent in the CUK specimens at all time points. Apical tubular MCP-1 expression, on immunolabeling, was present from 12 through 96 h after UUO in the obstructed kidney but not the CUK specimen. On Northern analysis, there were highly significant 2.6-, 5.8-, and 7.0-fold increments in renal cortical TGF-beta 1 mRNA levels at 12, 48, and 96 h, respectively, in the obstructed kidney versus the CUK specimen. Intracellular TGF-beta 1, on immunolabeling, was detected only in the obstructed kidneys of UUO rats at all three time points and was confined to peritubular cells of the renal interstitium. A significant (P < 0.005) correlation (r = 0.95) between interstitial macrophage number and cortical TGF-beta 1 mRNA levels was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

The cellular processes responsible for the proteinuria induced by the aminonucleoside of puromycin (PA) remain inadequately defined. Hypoxanthine is both a metabolic breakdown product of PA as well as a substrate for xanthine oxidase, which catalyzes its enzymatic conversion to xanthine and uric acid, yielding the superoxide anion in the process. We examined whether oxygen free radical production contributes to the development of proteinuria in this model. Seven groups of male Sprague-Dawley rats were studied. Proteinuria was quantitated and histology examined 7 days after rats were treated with PA intravenously over 5 min. PA-treated animals received either saline, dimethyl sulfoxide, superoxide dismutase, or catalase over 30 min prior to and 30 min following PA administration. Another group received allopurinol over 4 hr prior to PA. The superoxide dismutase and allopurinol treatment groups had a significant suppression of urinary protein excretion compared to the PA control group. There were also less severe glomerular morphologic changes in the superoxide dismutase group vs. the PA controls, which demonstrated a pathologic pattern that included epithelial cell blebbing, segmental mesangial cell proliferation and matrix expansion, loss of glomerular capillary lumina, and occasional adhesions between the glomerular tuft and Bowman's capsule. The allopurinol group exhibited normal glomerular morphology on light microscopy, with the exception of occasional epithelial cell blebs. All groups showed spreading of the epithelial cell cytoplasm along the glomerular basement membrane with loss of foot processes, focal areas of lifting of the epithelial cell from the glomerular basement membrane, cytoplasmic vacuolization, and protein reabsorption droplets; however, allopurinol-treated animals demonstrated these changes to a lesser extent.(ABSTRACT TRUNCATED AT 250 WORDS)