PMC:4548004 / 9749-18041
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{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4548004","sourcedb":"PMC","sourceid":"4548004","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4548004","text":"Results\n\nMetabolic parameters\nMetabolic parameters were measured to confirm whether human apoB Tg. SHR-cp/cp rats met the criterion for metabolic syndrome. Thirty-six-week-old male human apoB Tg. SHR-cp/cp rats showed higher body weight levels when fed the western diet than human apoB Tg. SHR-+/+ and non-Tg. SHR-+/+ rats (Table 1\nTable 1. Metabolic parameters in human apoB Tg. SHR-cp/cp rats\nApoB Tg. cp/cp Non-Tg. cp/cp ApoB Tg. +/+ Non-Tg. +/+\nn 9 8 7 7\nBody weight (g) 911 ± 20.8 963 ± 8.6 520 ± 15.5** 541 ± 11.9**\nPlasma insulin (ng/ml) 35 ± 5.9 23 ± 1.6 3 ± 0.2** 3 ± 0.3**\nPlasma glucose (mg/dl) 202 ± 33.8 203 ± 26.9 129 ± 2.7 145 ± 2.5\nPlasma TC (mg/dl) 1,513 ± 89.1 176 ± 9.2** 465 ± 10.1** 73 ± 1.8**\nPlasma TG (mg/dl) 1,044 ± 61.4 313 ± 149.9** 361 ± 12.8** 82 ± 10.5**\nPlasma human apoB (mg/dl) 1,147 ± 40.2 0 ± 0** 406 ± 11.6** 0 ± 0**\nPlasma HDL-c (mg/dl) 18 ± 2.1 40 ± 2.3** 5 ± 0.3** 24 ± 1.0\nSystolic blood pressure (mmHg) 139 ± 9.0 153 ± 2.0 150 ± 3.0 168 ± 4**\nData are shown as the mean ± SE. **P\u003c0.01 compared with human apoB Tg.-cp/cp rats.). There were no significant differences in body weight between human apoB Tg. SHR-cp/cp rats and non-Tg. SHR-cp/cp rats (Table 1). Twelve-week-old male human apoB Tg. SHR-cp/cp rats showed higher plasma insulin levels when fed the western diet than human apoB Tg. SHR-+/+ and non-Tg. SHR-+/+ rats after overnight fasting, although there were no significant differences in plasma glucose levels between the 4 strains (Table 1). There were no significant differences in plasma insulin levels between human apoB Tg. SHR-cp/cp rats and non-Tg. SHR-cp/cp rats (Table 1). Twelve-week-old human apoB Tg. SHR-cp/cp rats showed plasma total cholesterol (TC) and TG levels of more than 1,000 mg/dl when fed the MF-based western diet beginning at 8 weeks old. Then human apoB Tg. SHR-cp/cp rats showed stable hyperlipidemia during the experimental period (Supplemental Fig. 1). Thirty-six-week-old male human apoB Tg. SHR-cp/cp rats also showed higher total plasma TC, TG, and human apoB levels when fed the western diet than their littermates, human apoB Tg. SHR-+/+, non-Tg. SHR-cp/cp, and non-Tg. SHR-+/+ rats (Table 1). Plasma human apoB protein was detected in only human apoB Tg. rats (Table 1). Thirty-six-week-old male human apoB Tg. SHR-cp/cp rats showed lower plasma HDL-cholesterol levels when fed the western diet than non-Tg. SHR-cp/cp rats (Table 1). Systolic blood pressure (SBP) in each strain was measured by the tail-cuff method in 12-week-old rats, and there were no significant differences among human apoB Tg. SHR-cp/cp, human apoB Tg. SHR-+/+, and non-Tg. SHR-cp/cp rats (Table 1). However, non-Tg. SHR-+/+ rats showed a significantly higher SBP than human apoB Tg. SHR-cp/cp rats. The human apoB transgene had no effect on metabolic parameters, obesity, diabetes, or hypertension, with the exception of hyperlipidemia.\n\nUrinary albumin excretion, urinary protein excretion, and BUN\nUrinary albumin and protein excretion (UAE and UPE) and BUN were measured in 12-, 20-, 28- and 36-week-old rats. UAE and UPE in male human apoB Tg. SHR-cp/cp rats were more prominent earlier than in non-Tg. SHR-cp/cp rats; when they were fed the western diet (Figs. 1A and 1B\nFig. 1. (A)Urinary albumin excretion (UAE), (B) urinary protein excretion (UPE), and (C) BUN of rats. Filled circles and solid line, human apoB Tg. SHR-cp/cp (n=9); open circles and solid line, non-Tg. SHR-cp/cp (n=8); filled circles and dashed line, human apoB Tg. SHR-+/+ (n=7); and open circles and dashed line, non-Tg. SHR-+/+ rats (n=7). The asterisks indicate a significant difference at **P\u003c0.01 in comparison of human apoB Tg. SHR-cp/cp rats with non-Tg. SHR-cp/cp rats.). BUN gradually increased in human apoB Tg. SHR-cp/cp rats in accordance with increases in UAE and UPE, but this did not occur in the non-Tg. SHR-cp/cp rats (Fig. 1C).\n\nKIM1, Spp1, TBARS, and CRP\nKidney injury markers, an oxidative stress marker, and inflammation markers were measured in 36-week-old rats. KIM1 is located in the renal proximal tubule epithelial cells, and urinary KIM1 is a specific biomarker for tubular injury. Thirty-six-week-old male human apoB Tg. SHR-cp/cp rats showed higher urinary KIM1 levels when fed the western diet than an established diabetic nephropathy model, non-Tg. SHR-cp/cp rats (Fig. 2A\nFig. 2. Kidney injury, oxidative, and inflammation marker levels in 36-week-old of human apoB Tg. SHR-cp/cp (n=9), non-Tg. SHR-cp/cp (n=8), human apoB Tg. SHR-+/+ (n=7), and non-Tg. SHR-+/+ rats (n=7). (A) Urinary KIM1 excretion, (B) Spp1 mRNA expression in the kidney cortex, (C) plasma thiobarbituric acid reactive substances (TBARS), and (D) plasma C-reactive protein (CRP) levels. The asterisks indicate a significant difference at *P\u003c0.05 or **P\u003c0.01 in comparison of human apoB Tg. SHR-cp/cp rats with their littermates.). SPP1 is a pleiotropic cytokine that is ubiquitously expressed and upregulated during inflammation. Thirty-six-week-old male human apoB Tg. SHR-cp/cp rats also showed increased Spp1 mRNA expression levels in the renal cortex; compared with non-Tg. SHR-cp/cp rats (Fig. 2B). The plasma levels of TBARS, an oxidative stress marker and an index for lipid peroxidation are shown in Fig. 2C. Thirty-six-week-old male human apoB Tg. SHR-cp/cp rats showed more than a three-fold increase in TBARS levels than their littermates, human apoB Tg. SHR-+/+, non-Tg. SHR-cp/cp, and non-Tg. SHR-+/+ rats (Fig. 2C). The plasma levels of CRP, a sensitive marker for inflammation, are shown in Fig. 2D. Thirty-six-week-old male human apoB Tg. SHR-cp/cp rats showed significantly increased plasma hsCRP levels than those of their littermates, human apoB Tg. SHR-+/+, non-Tg. SHR-cp/cp, and non-Tg. SHR-+/+ rats (Fig. 2D).\n\nRenal histology\nRepresentative histological features of 36-week-old male human apoB Tg. SHR-cp/cp rats are shown in Fig. 3\nFig. 3. Representative light micrographs of H\u0026E- (A-D), PAM- (E-H), and Oil Red O-stained (I, J) kidney sections from 36-week-old human apoB Tg. SHR-cp/cp (A, E, I), non-Tg. SHR-cp/cp (B, F, J), human apoB Tg. SHR-+/+ (C, G), and non-Tg. SHR-+/+ rats (D, H). Filled circles indicate hyaline casts. Arrows indicate dilated tubules. In the sections stained with Oil Red O (I, J), lipid droplets appeared as red spots and indicate the accumulation of neutral lipids in the glomeruli. K: The glomerulosclerosis score of the rats is shown. The number of rats is shown in parentheses. Values are shown as the mean ± SEM. Bars=100 μm. The asterisks indicate a significant difference at ††P\u003c0.01 compared with the human apoB Tg. SHR-cp/cp rats.. Human apoB Tg. SHR-cp/cp rats showed prominent hyaline casts and tubular degeneration/regeneration. The tubular changes were characterized by vacuolation and single-cell necrosis of the tubular epithelium, thickening of the basement membrane and tubular dilation. Mononuclear cell infiltration mainly consisting of lymphocytes was also observed in the interstitial region (Fig. 3A). These lesions were also seen in non-Tg. SHR-cp/cp rats (Fig. 3B); however, the severities in human apoB Tg. SHR-cp/cp rats were significantly higher than those in non-Tg. SHR-cp/cp rats (Table 2\nTable 2. Quantitative analysis of tubulointerstitial lesions in human apoB Tg. SHR-cp/cp rats\nApoB Tg. cp/cp Non-Tg. cp/cp ApoB Tg. +/+ Non-Tg. +/+\nn 9 8 7 7\nTubular degeneration/regeneration 2.9 ± 0.1 2.1 ± 0.1* 0.7 ± 0.2** 0.6 ± 0.2**\nMononuclear cell infiltration 2.8 ± 0.2 1.8 ± 0.2* 0.1 ± 0.2** 0.1 ± 0.2**\nHyaline cast 2.9 ± 0.1 2.3 ± 0.2* 0.9 ± 0.2** 0.7 ± 0.2**\nData are shown as the mean ± SE. *P\u003c0.05 and **P\u003c0.01 compared with human apoB Tg.-cp/cp rats.). Human apoB Tg. SHR-cp/cp rats also showed more severe glomerulosclerosis compared with non-Tg. SHR-cp/cp rats (Figs. 3E and 3F), and the glomerulosclerosis score in human apoB Tg. SHR-cp/cp rats was significantly higher than that in non-Tg. SHR-cp/cp rats (Fig. 3K). Few lipids were observed in the glomeruli of non-Tg. SHR-cp/cp rats (Fig. 3J), whereas more prominent lipid accumulation was observed in the glomeruli of all the human apoB Tg. SHR-cp/cp rats (Fig. 3I). Human apoB Tg. SHR-+/+ rats and non-Tg. SHR-+/+ rats showed no remarkable glomerular or tubulointerstitial changes (Figs. 3C, 3D, 3G, and 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