Kaihui Liang

Lead-induced hypertension. III. Increased hydroxyl radical production

Lead-induced hypertension has previously been shown to be closely associated with an increase in reactive oxygen species in low lead (100 ppm)-treated rats. The present study has attempted to define the specific moiety involved by noting the blood pressure (BP), reactive oxygen species (MDA-TBA), hydroxyl radical, and nitrotyrosine responses to infusion of the reactive oxygen species scavenger dimethylthiourea. Dimethylthiourea, a reputed scavenger of hydroxyl radical, normalized BP and MDA-TBA in the lead-treated rats but had no effect in normal control animals. MDA-TBA, hydroxyl radical, and nitrotyrosine, the tissue end product of peroxynitrite, were reduced to or toward normal by dimethylthiourea. The results, therefore, are consistent with the suggestion that either hydroxyl radical or peroxynitrite may be the reactive species affected by lead.

Secondary hyperparathyroidism downregulates lipoprotein lipase expression in chronic renal failure.

In a recent study, we found marked downregulation of lipoprotein lipase (LPL) gene expression in fat, myocardium, and skeletal muscle of rats with chronic renal failure (CRF). Recently, hepatic lipase expression was shown to be depressed in CRF rats, and parathyroidectomy (PTX) was shown to reverse this abnormality. This study was undertaken to determine whether downregulation of LPL expression in CRF is due to secondary hyperparathyroidism. Accordingly, LPL mRNA (Northern analysis), protein mass (Western analysis using mouse anti-bovine LPL monoclonal antibody, 5D2), and catalytic activity of the fat pad and soleus muscle were compared in five-sixths-nephrectomized male rats (CRF), parathyroidectomized CRF rats, and sham-operated control animals. The CRF animals exhibited marked hypertriglyceridemia and significant reductions of fat and skeletal muscle LPL mRNA abundance, protein mass, and catalytic activity ( P < 0.05 vs. controls, for all parameters). PTX completely normalized the LPL mRNA, protein mass, and enzymatic activity and partially ameliorated the CRF hypertriglyceridemia ( P < 0.05 vs. CRF group, for all parameters). Thus secondary hyperparathyroidism is responsible for impaired LPL expression in experimental CRF. This abnormality is completely corrected by PTX.In a recent study, we found marked downregulation of lipoprotein lipase (LPL) gene expression in fat, myocardium, and skeletal muscle of rats with chronic renal failure (CRF). Recently, hepatic lipase expression was shown to be depressed in CRF rats, and parathyroidectomy (PTX) was shown to reverse this abnormality. This study was undertaken to determine whether down-regulation of LPL expression in CRF is due to secondary hyperparathyroidism. Accordingly, LPL mRNA (Northern analysis), protein mass (Western analysis using mouse antibovine LPL monoclonal antibody, 5D2), and catalytic activity of the fat pad and soleus muscle were compared in five-sixths-nephrectomized male rats (CRF), parathyroidectomized CRF rats, and sham-operated control animals. The CRF animals exhibited marked hypertriglyceridemia and significant reductions of fat and skeletal muscle LPL mRNA abundance, protein mass, and catalytic activity (P < 0.05 vs. controls, for all parameters). PTX completely normalized the LPL mRNA, protein mass, and enzymatic activity and partially ameliorated the CRF hypertriglyceridemia (P < 0.05 vs. CRF group, for all parameters). Thus secondary hyperparathyroidism is responsible for impaired LPL expression in experimental CRF. This abnormality is completely corrected by PTX.

Gene expression of lipoprotein lipase in experimental nephrosis

Nephrotic syndrome (NS) is commonly associated with marked hypertriglyceridemia, impaired triglyceride-laden lipoprotein clearance, and reduced peripheral tissue uptake of triglycerides from chylomicrons. Lipoprotein lipase (LPL) is the rate-limiting step in triglyceride-rich lipoprotein metabolism. Earlier studies have demonstrated a marked reduction of plasma post-heparin lipolytic activity and LPL protein in NS. However, the effect of NS on gene expression of LPL has not been elucidated. We studied rats with puromycin aminonucleoside-induced NS and the placebo-injected control animals. Heart, soleus muscle, and fat body LPL activity, protein mass, and mRNA were measured and plasma lipid levels were quantitated. The NS group exhibited marked proteinuria, hypoalbuminemia, and hypertriglyceridemia. This was associated with significant reductions of LPL activity and immunodetectable protein in the heart, adipose tissue, and soleus muscle in the NS group. The reduction in LPL protein mass in the tissues tested was accompanied by a parallel reduction in LPL mRNA of the heart but not of either adipose tissue or skeletal muscle, suggesting translational or posttranslational modifications. A negative correlation was found between plasma triglyceride concentration and the LPL, activities of the tissues tested in the study population. Thus this study has revealed a significant down-regulation of tissue LPL protein in experimental NS. This phenomenon can, in part, account for hypertriglyceridemia, impaired catabolism of chylomicrons, and very low-density lipoprotein by peripheral tissues and decreased postheparin lipolytic activity in NS.

Effects of HMG-CoA Reductase Inhibition on Hepatic Expression of Key Cholesterol-Regulatory Enzymes and Receptors in Nephrotic Syndrome

Background: Hypercholesterolemia is one of the major manifestations of nephrotic syndrome. We have previously shown that nephrotic hypercholesterolemia is associated with and, in part, due to dysregulation of hepatic HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase (ACAT) and cholesterol 7α-hydroxylase, as well as lecithin:cholesterol acyltransferase (LCAT), low-density lipoprotein (LDL) receptor and high-density lipoprotein (HDL) receptor deficiencies. This study was carried out to discern the effect of inhibition of HMG-CoA reductase on expression of the key enzymes and receptors involved in cholesterol metabolism in the liver. Methods: Rats with puromycin-induced nephrotic syndrome were treated with either a statin (rosuvastatin 20 mg/kg/day) or placebo for 2 weeks. Placebo-treated normal rats served as controls. Gene expression, protein abundance and/or activities of relevant receptors and enzymes were quantified. Results: The untreated nephrotic rats showed heavy proteinuria, hypoalbuminemia, hypercholesterolemia, elevated total cholesterol:HDL cholesterol ratio and normal creatinine clearance. This was associated with severe reductions in hepatic LDL receptor, hepatic HDL receptor and plasma LCAT concentration, marked upregulation of hepatic ACAT, and unchanged cholesterol 7α-hydroxylase (rate-limiting step in cholesterol catabolism). Statin administration for 2 weeks ameliorated hepatic LDL receptor and HDL receptor deficiencies and significantly lowered plasma cholesterol, LDL cholesterol, total cholesterol:HDL cholesterol ratio and proteinuria. Conclusions: HMG-CoA reductase inhibition improved hepatic LDL and HDL receptor deficiencies, and ameliorated the associated hyperlipidemia in the nephrotic rats.

Effect of increased afterload on cardiac lipoprotein lipase and VLDL receptor expression

Fatty acids are a major source of fuel for energy production by myocytes. Lipoprotein lipase (LPL) and very low density lipoprotein (VLDL) receptor are abundantly expressed by the heart and skeletal muscles. LPL and possibly VLDL receptor represent the primary route of access to fatty acids contained in circulating triglyceride-rich lipoproteins. Physical exercise and thyroid hormone, which promote energy consumption, upregulate LPL expression in skeletal muscles. This study tested the hypothesis that increased cardiac workload might modulate myocardial LPL and/or VLDL receptor expressions. Accordingly, cardiac tissue LPL activity, LPL and VLDL receptor proteins and mRNA abundance were studied in Sprague-Dawley rats 4 weeks after induction of severe thoracic aorta constriction or sham operation. Elevation of afterload with thoracic aortic constriction led to a significant cardiomegaly and a marked upregulation of cardiac LPL activity, LPL mRNA and LPL protein abundance, but did not modify VLDL receptor mRNA or protein abundance. Thus, increased cardiac workload in this model results in upregulation of myocardial LPL expression which can enhance fatty acid availability to accommodate the hearts increased energy requirement.