OBJECTIVETo determine the effect of hypercholsterolemia induced by a high-lipid diet on glomerulosclerosis.

METHODSTwenty nephrotic syndrome (NS) Wistar rats administrated adriamycin (ADR) with a single intravenous dose of 5 mg/kg body weight, were divided into the standard and high-lipid chow groups. Another 20 weight-matched non-NS rats that received a vehicle alone were grouped as control. Urinary protein excretion and serum cholesterol were assayed; image analysis and techniques of pathology, immunohistochemistry, and molecular biology were used to determine morphological changes in glomeruli and the production of glomerular mesangial matrices in different groups.

RESULTSThe serum total cholesterol level was significantly higher in rats with high-lipid chow in both non-NS [(2.2 +/- 0.3) g/L vs. (0.9 +/- 0.1) g/L, P < 0.01] and NS [(9.5 +/- 0.2) g/L vs. (2.3 +/- 0.3) g/L, P < 0.01]. The urinary protein excretion was significantly higher in the high-lipid diet rats than in standard chow rats [(76.2 +/- 24.2) mg/24h vs. (44.8 +/- 13.6) mg/24h, P < 0.05] in NS rats. Although increases in the mesangial matrix and mesangial cells were observed in rats with high-lipid diet in both NS and non-NS group, more obvious pathological changes were found in NS group, such as lipid deposits and foam cell formation in mesangial areas, and progressing to focal and segmental glomerulosclerosis in some glomeruli. The immunohistochemical asay showed that the production of 3 major components (collagen IV, fibronectin, and laminin) was increased in NS group, especially in the rats with high-lipid chow. The increased expression of laminin mRNA was also detected with slot blotting in both NS and non-NS rats with high-lipid chow, and it was more obvious in the rats with NS.

CONCLUSIONOur findings indicated that diet-induced hyperlipidemia can lead to over-production of mesangial matrix components, and further aggravate glomerulosclerosis in ADR-induced nephrosis.

Animals ; Dietary Fats ; pharmacology ; Doxorubicin ; Fibronectins ; metabolism ; Glomerular Mesangium ; metabolism ; pathology ; Hypercholesterolemia ; metabolism ; Laminin ; metabolism ; Male ; Nephrotic Syndrome ; chemically induced ; metabolism ; pathology ; Proteinuria ; urine ; Rats ; Rats, Wistar

In our previous study, two point mutants of apolipoprotein A-I, designated V156K and A158E, revealed peculiar characteristics in their lipid-free and lipid-bound states. In order to determine the putative therapeutic potential of these mutants, several in vitro and in vivo evaluations were conducted. In the lipid-free state, V156K showed more profound antioxidant activity against LDL oxidation than did the wildtype (WT) or A158E variants in an in vitro assay. In the lipid-bound state, V156K-rHDL showed an enhanced cholesterol delivery activity to HepG2 cells in a time-dependent manner, as compared to WT-rHDL, A158E-rHDL, and R173C-rHDL. We assessed the physiological activities of the mutants in circulation, using hypercholesterolemic mice (C57BL6/J). Palmitoyloleoyl phosphatidylcholine (POPC)-rHDL preparations containing each of the apoA-I variants were injected into the mice at a dosage of 30 mg of apoA-I/kg of body weight. Forty eight hours after injection, the sera of the V156K-rHDL injected group showed the most potent antioxidant abilities in the ferric acid removal assay. The V156K-rHDL- or R173C-rHDL-injected mice showed no atherosclerotic lesions and manifested striking increases in their serum apo-E levels, as compared to the mice injected with WT-rHDL or A158E-rHDL. In conclusion, V156K-rHDL exhibited the most pronounced antioxidant activity and anti-atherosclerotic activity, both in vitro and in vivo. These results support the notion that HDL-therapy may prove beneficial due to its capacity to induce accelerated cholesterol excretion, as well as its enhanced antioxidant and anti-inflammatory effects and lesion regression effect.
Amino Acids/*genetics ; Animals ; Antioxidants/*metabolism ; Apolipoprotein A-I/*genetics ; Atherosclerosis/*pathology ; Biological Transport/drug effects ; Cell Line, Tumor ; Cholesterol/metabolism ; Copper/pharmacology ; Humans ; Hypercholesterolemia/chemically induced/*pathology ; Lipoproteins, HDL/blood ; Lipoproteins, LDL/blood ; Male ; Mice ; Mice, Inbred C57BL ; Oxidation-Reduction/drug effects ; Point Mutation/*genetics ; Recombinant Proteins/blood

OBJECTIVETo study the influence of beta-amyloid protein (Abeta) and cholesterol on the pathological changes of Alzheimer's disease (AD) and on the expression of nicotinic acetylcholine receptor (nAChR) subunits in the brains of rats.

METHODThe rats were treated by intracerebroventricular injection of Abeta1-42 and fed with a diet containing 5% cholesterol to establish animal model of AD. The pathological changes, learning and memory, and expression of nAChRs of rats were analyzed by Bieoschowsky staining, immunohistochemistry, water-labyrinth, Western blot, and RT-PCR.

RESULTSAbeta intracerebroventricular injection induced Abeta deposition in rat brains and high-cholesterol diet resulted in hypercholesterolemia in the animals. Injection of Abeta caused a reduction of learning and memory of rats and modifications of the expression of nAChRs. Cholesterol enhanced these effects of Abeta on neuropathology and expression of nAChRs.

CONCLUSIONSAbeta can induce marked neuropathological changes, influence the learning and study ability, and modify the expression of nAChRs. Cholesterol can enhance the neurotoxicity of Abeta.

Alzheimer Disease ; chemically induced ; metabolism ; pathology ; physiopathology ; Amyloid beta-Peptides ; metabolism ; Animals ; Cerebral Cortex ; metabolism ; pathology ; Cholesterol ; blood ; Drug Synergism ; Female ; Hypercholesterolemia ; blood ; Learning ; drug effects ; Male ; Peptide Fragments ; metabolism ; RNA, Messenger ; metabolism ; Random Allocation ; Rats ; Rats, Wistar ; Receptors, Nicotinic ; biosynthesis ; genetics