Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serial changes in urine protein, blood chemistry, and histology of the kidney were investigated in rats for 28 weeks after injections of adriamycin (ADR). Massive proteinuria, hypoalbuminemia, and hyperlipidemia were observed at week 4 and throughout the experiment. Both BUN and serum creatinine began to increase at week 16 and reached the uremic level at week 28. Light microscopic study of the kidney demonstrated a normal appearance at week 4, vacuole formation in glomerular tuft at weeks 8 and 12, focal and segmental glomerular sclerosis at weeks 16 and 20, and extensive glomerular sclerosis with tubulointerstitial degenerations at weeks 24 and 28. Immunohistologically, IgM with a small amount of IgG and C3 appeared in the sclerosing glomeruli from week 16. Aggregated human IgG, injected intravenously at week 24, had accumulated mainly in the glomeruli. Electron microscopy revealed degenerative changes of glomerular epithelial cells with small vacuoles in the cytoplasm at week 4. Size of vacuoles increased at the later stage. In conclusion, ADR produced chronic, progressive glomerular changes in rats, which led to terminal renal failure. The segmental glomerular sclerosis and IgM-dominant glomerular deposition in these animals are similar to pathological characteristics of focal and segmental glomerular sclerosis seen clinically.
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PMID:Adriamycin-induced nephropathy as a model of chronic progressive glomerular disease. 348 12

Advances in our understanding of the mechanisms of proteinuria in humans have depended on a variety of animal models. Most of these have been partially satisfactory because they require pretreatment of the animal with chemicals or toxins or they depend on an aging-related glomerular protein leakiness. The strain in this study was obtained by Koletsky after selective inbreeding of the offspring from a hypertensive Kyoto-Wistar and a normotensive Sprague-Dawley rat. The affected animals appear in 25% of the litters, indicating an autosomal recessive gene, and present with a spontaneous and progressive nephrotic syndrome detected as early as 3-5 weeks and associated with obesity, hypertension, hypoalbuminemia, hypercholesterolemia, and hyperlipidemia. Preliminary morphologic and immunofluorescence studies of their kidneys show progressive glomerular segmental sclerotic lesions and prominent mesangial deposition of IgM, a picture which resembles a steroid-resistant form of idiopathic nephrotic syndrome in humans, namely, focal glomerular sclerosis.
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PMID:Spontaneous nephrotic syndrome in a genetic rat model. 650 87

Genetically obese and hypertensive rats (Obese/SHR) were subjected to sham or bilateral adrenalectomy at 4-5 weeks of age with the onset of hyperphagia. The sham-operated Obese/SHR ate voraciously and by 180 days of age males weighed 700 g and females 590 g. The adrenalectomized Obese/SHR ate much less and weighed 325 and 225 g. The systolic blood pressure of the intact Obese/SHR ranged from 160 to 170 mmHg, whereas the blood pressure of the adrenalectomized animals ranged from 108 to 110 mmHg. The thymi of the intact Obese/SHR were massive compared to those of the adrenalectomized rats. Adrenalectomy effectively reduced the hyperinsulinaemia, adiposity, hyperlipidaemia, hyperglycaemia, and elevated BUN levels of the obese rats. Several obese rats had old or new myocardial infarcts, fatty livers, giant-sized islets of Langerhans, nodular and hyperaemic adrenal glands, narrow zona glomerulosa devoid of lipid, vacuolated inner cortical zones, foci of intimal fibrinohyalin deposits in mesenteric arteries, early glomerulosclerosis, and large, rounded bladder calculi. The adrenalectomized Obese/SHR displayed none of these stigmata. It is suggested that the genetically programmed obesity and hypertension in these SHR are mediated by abnormal activity of the hypothalamic-pituitary-adrenal-gonadal axis, may be likened to Cushing's disease in the human, and is associated with accelerated ageing.
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PMID:Ameliorative effects of adrenalectomy on the hyperphagia, hyperlipidaemia, hyperglycaemia and hypertension of obese, spontaneously hypertensive rats (Obese/SHR). 701 60

Left ventricular hypertrophy with diffuse intermyocardiocytic fibrosis is a feature of uremia. The role of blood pressure and/or other cardiovascular uremic risk factors in cardiac remodeling is still uncertain. To determine the extent to which improvement of kidney function and the control of uremia-related risk factors are associated with a reduction of myocardial injury, we evaluated the effect of dietary protein restriction or the angiotensin-converting enzyme inhibitor lisinopril on cardiac structure in remnant kidney rats. One week after subtotal nephrectomy, Wistar rats were allocated to receive drinking water solution (group 1), 5 mg/kg per day lisinopril (group 2), or a low-protein diet (6%) (group 3) for 12 weeks. Group 2 and 3 showed a comparable efficacy in preventing the expected rise in creatininemia, urinary protein excretion, and glomerulosclerosis. However, hypertension development was prevented only in group 2. Groups 1 and 3 developed a significant (P < .01) increase in left ventricular weight (2.45 +/- 0.1 and 2.5 +/- 0.5 mg/g body wt, respectively) compared with group 2 (1.9 +/- 0.06 mg/g body wt). Cardiac hydroxyporline concentration was also lower in group 2 compared with group 1 (2.07 +/- 0.16 versus 2.73 +/- 0.17 mg/g left ventricular weight, P < .05) but not compared with group 3 (2.59 +/- 0.19 mg/g left ventricular weight). The effect of angiotensin-converting enzyme inhibition on left ventricular mass and intracardiac collagen content appeared to be dissociated from anemia, sympathetic activity, and hyperlipidemia. There was a close relationship between systolic pressure and left ventricular mass; however, no relationship between the degree of cardiac fibrosis and systolic pressure could be determined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution of systemic blood pressure to myocardial remodeling in uremic rats. 763 42

The effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the metabolism of apolipoprotein (apo) B-containing lipoproteins appear to differ according to the predominant lipoprotein profiles present and the condition being treated. In familial hypercholesterolemia, with isolated low density lipoprotein (LDL) elevations, the LDL-apoB elimination rate is increased by up-regulated LDL-receptors. In familial combined hyperlipidemia where very low density lipoprotein (VLDL) and LDL both may be increased and enhanced production of LDL-apoB may be present, HMG-CoA reductase inhibitors seem to diminish increased LDL-apoB production. The drug-induced decreases in LDL-apoB production could be due to decreased production of precursor VLDL-apoB or due to decreased conversion of VLDL-apoB to LDL-apoB after enhanced removal of VLDL by up-regulated LDL-receptors. To distinguish between these possibilities, we assessed the effects of HMG-CoA reductase inhibitors in another condition in which there is both apoB overproduction and accumulation of VLDL and LDL in plasma, the nephrotic syndrome. We used endogenous labeling of apoB with [13C]leucine and a multicompartmental model to calculate the metabolic parameters of apoB-containing lipoproteins. Only subjects with focal segmental glomerular sclerosis (FSGS) were included, as FSGS is a chronic, very slowly progressive form of nephrotic syndrome. A double-blind, randomized, placebo-controlled, crossover design was used. Treatment periods of 6 weeks were separated by a 2-week washout period. Of the four men studied, three had high triglyceride levels and four had high cholesterol levels. Lovastatin (20 mg/day) significantly decreased cholesterol (27.6 +/- 6%), LDL-cholesterol (27.6 +/- 9%) and plasma apoB (17.9 +/- 2.9%) (P < 0.01 for all). During the placebo period, calculation of kinetic parameters revealed VLDL-, intermediate density lipoprotein (IDL)-, and LDL-apoB overproduction and decreased VLDL-apoB fractional catabolic rate. Lovastatin significantly decreased LDL-apoB production rate in all cases (34.1 +/- 14%, P = 0.03). The decreased LDL-apoB was mainly due to a channelling of LDL precursors away from conversion to LDL (conversion of VLDL to LDL decreased from 80.6 +/- 8.3% to 55.9 +/- 17.2%, P = 0.05). Thus, lovastatin decreased LDL-cholesterol in nephrotic subjects mainly by inhibiting LDL-apoB production from VLDL.
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PMID:Physiologic mechanisms of action of lovastatin in nephrotic syndrome. 770 43

To elucidate the pathogenetic role of hyperlipidemia per se in the development of glomerulosclerosis, severely hyperlipidemic female analbuminemic rats (NAR) and mildly hyperlipidemic male NAR were studied for a period of 37 weeks after uninephrectomy (UNX). Plasma cholesterol increased from 6.3 +/- 0.4 (week 4) to 11.9 +/- 0.6 mmol/liter (week 37) in the female NAR, and from 4.3 +/- 0.1 to 6.4 +/- 0.5 mmol/liter in the male NAR in the same period. Plasma protein concentration was also consistently higher in female NAR (60 +/- 1 g/liter) as compared to male NAR (52 +/- 1 g/liter). Plasma viscosity was higher in female NAR than in male NAR, but there were no differences in blood viscosity. Proteinuria increased progressively in the UNX female NAR from 25 weeks after surgery, reaching a final value of 141 +/- 37 mg/day. No proteinuria occurred in the UNX male NAR (final value 15 +/- 2 mg/day). Glomerular capillary pressure, measured prior to the onset of proteinuria, was not significantly different in UNX female NAR and UNX male NAR. At the end of the study glomerulosclerosis and lipid deposition was only found in the UNX female NAR. Throughout the study hyperfiltration and hyperperfusion, relative to the one-kidney clearances of the sham-operated (2K) animals, were not different in UNX male and female NAR. No differences were observed in blood pressure. Hypertrophy, evaluated by glomerular diameters, was less pronounced in UNX female NAR (174 +/- 3 microns) than in UNX male NAR (190 +/- 7 microns). Glomerular diameters in 2K female and male NAR were similar (respectively 158 +/- 2 and 157 +/- 4 microns). Plasma apo B levels were similar (2K female NAR: 204 +/- 8 U; 2K male NAR 204 +/- 13 U), but cholesterol and triglyceride content of apo B-containing lipoproteins, namely VLDL, IDL and LDL, was increased twofold in the female NAR as compared to the male NAR, implying a larger particle size in the female NAR. Deposition of apo B and apo E was observed in the glomerular mesangium of UNX female NAR, particularly in sclerotic lesions. Glomerular apo A-I deposits were localized primarily in visceral epithelial cells and were not associated with sclerotic lesions. The development of proteinuria and glomerulosclerosis after UNX in female NAR but not in male NAR may depend upon differences in plasma lipoprotein composition, but is apparently not related to differences in whole kidney hyperfiltration and hyperperfusion, glomerular capillary pressure, or blood viscosity.
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PMID:Proteinuria, lipoproteins and renal apolipoprotein deposits in uninephrectomized female analbuminemic rats. 772 32

Spontaneously hypercholesterolemic (SHC) rats become hypercholesterolemic on normal diets. SHC rats, especially males, exhibit renal lesions similar to those found in focal segmental hyalinosis/sclerosis (FGS). We presented here a detailed natural history of serum lipid, renal function and pathological changes in male SHC rats from 5 to 40 weeks of age. Increased urinary protein excretion and glomerular injury were apparent before the detection of lipid or immune deposits, indicating that the renal lesions were not caused by these deposits. Serum total cholesterol levels, already high at 5 weeks, abruptly increased in concurrence with increased urinary protein excretion, suggesting that the severe hyperlipidemia of this strain is modified by a nephrotic syndrome. By 30 weeks of age, glomerular sclerosis was evident in more than half of the glomeruli and tubular dilatation was prominent, with an abrupt increase of BUN, SCr, and urinary volume; these findings indicate a rapid progression to renal failure. Our results suggest that SHC rats would be a very useful model to investigate the process leading to glomerular sclerotic lesion and renal failure, as well as the effect of hyperlipidemia on glomerular injury.
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PMID:Natural history of renal lesions in spontaneously hypercholesterolemic (SHC) male rats. 775 9

The effect of d-alpha-tocopherol on the progression of renal dysfunction was investigated in rats injected with adriamycin (ADR), a model of progressive glomerulosclerosis associated with the nephrotic syndrome. Treatment with d-alpha-tocopherol was started 1 day before or 1 day after ADR injections (BE-TOC or AF-TOC rats). When compared to rats without d-alpha-tocopherol treatment (ADR-CON rats), the serum total cholesterol and triglyceride levels were significantly lower in the BE-TOC and AF-TOC groups. In week 16, the LDL cholesterol level and the atherogenic index were both significantly lower in BE-TOC and AF-TOC rats than in ADR-CON rats. The urinary protein, serum creatinine, blood urea nitrogen, malondialdehyde, and systolic blood pressure levels as well as the glomerulosclerosis score were high in ADR-CON rats, and reduced in BE-TOC or AF-TOC rats. There were no significant differences in body weight and serum albumin between the three groups in week 16. It is concluded that d-alpha-tocopherol can improve hyperlipidemia and ameliorate glomerulosclerosis in rats with ADR-induced progressive renal failure. Thus, d-alpha-tocopherol may have the potential for clinical application to treat focal glomerulosclerosis.
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PMID:Alpha tocopherol improves focal glomerulosclerosis in rats with adriamycin-induced progressive renal failure. 783 58

Hyperlipidemia of nephrotic origin could potentially cause glomerular injury as well as increase the risk of atherosclerosis. The precise interaction of human lipoproteins abnormal in lipid and protein composition, with lipoprotein receptors has not been clearly defined. This study examines receptor-mediated uptake and intracellular cholesterol metabolism of apolipoprotein (apo)B,E containing intermediate-density lipoprotein (IDL) and apoB-100 containing low-density lipoprotein (LDL), isolated from patients with the nephrotic syndrome (N = 6), in human glomerular mesangial and HepG2 cells. In the patients, serum IDL and LDL cholesterol levels were significantly increased as compared with those of healthy subjects. The IDL of nephrotic patients contained 80% more cholesterol than the IDL of healthy controls. No differences in lipid/protein composition were found in the LDL density range. Therefore, nephrotic and control LDL showed identical affinities for receptor-mediated uptake. In contrast, the IDL of nephrotic patients was taken up by mesangial cells and HepG2 with higher affinity than the LDL. Intracellular sterol synthesis was suppressed more effectively and cholesterol esterification rate was enhanced 2.2-fold by nephrotic IDL as compared with control IDL. These data indicate that hypercholesterolemia of nephrotic origin cannot be explained by reduced ligand binding for LDL. ApoE-containing IDL of patients with the nephrotic syndrome were avidly taken up by glomerular mesangial cells and could therefore play the predominant role in the development of glomerulosclerosis and atherosclerosis associated with this disorder.
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PMID:Preferential uptake of intermediate-density lipoproteins from nephrotic patients by human mesangial and liver cells. 784 47

Experiments in animal models suggest that correcting abnormalities in lipid metabolism could help slow the rate of functional decline in patients with chronic progressive renal disease. Circumstantial evidence in humans also suggests that lipids may play a role in the pathogenesis of glomerulosclerosis. Nevertheless, large controlled clinical trials examining the effect of lipid-lowering strategies on renal disease progression have not been carried out. However, the recent development of antilipemic agents that appear to be safe and effective in patients with renal disease should make it possible to determine whether treating hyperlipidemia will reduce the rate of renal disease progression.
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PMID:Treatment of hyperlipidemia in chronic progressive renal disease. 785 23


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