Cardiac remodeling associated with protein increase and lipid accumulation in early-stage chronic kidney disease in rats.

Chronic kidney disease (CKD) is associated with increased risks of cardiovascular morbidity and mortality. Cardiac remodeling including myocardial fibrosis and hypertrophy is frequently observed in CKD patients. In this study, we investigate the mechanism involved in cardiac hypertrophy associated with CKD using a rat model, by morphological and chemical component changes of the hypertrophic and non-hypertrophic hearts. Sprague-Dawley rats were 4/5 nephrectomized (Nx) at 11 weeks of age and assigned to no treatment and treatment with AST-120, which was reported to affect the cardiac damage, at 18 weeks of age. At 26 weeks of age, the rats were euthanized under anesthesia, and biochemical tests as well as analysis of cardiac condition were performed by histological and spectrophotometric methods. Cardiac hypertrophy and CKD were observed in 4/5 Nx rats even though vascular calcification and myocardial fibrosis were not detected. The increasing myocardial protein was confirmed in hypertrophic hearts by infrared spectroscopy. The absorption of amide I and other protein bands in hypertrophic hearts increased at the same position as in normal cardiac absorption. Infrared spectra also showed that lipid accumulation was also detected in hypertrophic heart. Conversely, the absorptions of protein were obviously reduced in the myocardium of non-hypertrophic heart with CKD compared to that of hypertrophic heart. The lipid associated absorption was also decreased in non-hypertrophic heart. Our results suggest that cardiac remodeling associated with relatively early-stage CKD may be suppressed by reducing increased myocardial protein and ameliorating cardiac lipid load.

Renal vascular structural properties and their alterations by removal of uraemic toxins in a rat model of chronic kidney disease.

1. Renal vascular structural properties and their alterations by removal of uraemic toxins with AST-120, an oral adsorbent, were examined in subtotal nephrectomized rats. 2. Eight- or 9-week-old Sprague-Dawley rats received 3/4 nephrectomy (n = 18) and thereafter were fed 24.5% protein diet with (AST; n = 9) or without (AST-; n = 9) AST-120 (0.4 g/100 g bodyweight). Sham-operated rats (Sham; n = 9) received the diet without AST-120. At 21-22 weeks of age, flow-pressure (F-P) and pressure-glomerular filtration rate (P-GFR) relationships were determined for maximally vasodilated, perfused kidneys. 3. The gradient of F-P (minimal renal vascular resistance reflecting the overall luminal dimensions of pre- and post-glomerular vasculature) was lower in AST- than Sham rats. In contrast, the x-intercept (preglomerular : post-glomerular vascular resistance ratio) and gradient (glomerular filtration capacity) of P-GFR did not differ between the two groups. The vascular wall and lumen at the interlobular arteries were greater in AST- than Sham rats. 4. Although the vascular wall and lumen at the interlobular arteries were less in AST than in AST- rats, the gradient of F-P and the x-intercept of P-GFR did not differ between the two groups. In contrast, the glomerular filtration capacity was greater in AST than AST- rats. 5. In conclusion, the lumen of both pre- and post-glomerular resistance vessels increased and glomerular filtration capacity failed to increase in subtotal nephrectomized rats. Uraemic toxins could play an important role in the development of structural alterations in glomeruli rather than renal resistance vessels in chronic kidney disease.

Dietary inorganic phosphorus regulates the intestinal peptide transporter PepT1.

BACKGROUND: Both organic and inorganic phosphorus (Pi) are present in regularly consumed foods, such as meats, eggs, and dairy products. Pi is often included in foods as an additive (as hidden phosphorus). The intestinal peptide transporter PepT1 mediates protein absorption, which is disturbed in renal insufficiency. Our aim was to determine the effects of dietary Pi content on the peptide transport activity and expression of PepT1. METHODS: The following animal models were used: (1) 7-week-old male Wistar rats; and (2) rats that underwent 3/4 nephrectomy to induce chronic kidney disease (CKD). The rats were fed a normal-protein (20%) diet containing low (0.02%), normal (0.6%), or high (1.2%) Pi levels. They were also fed diets containing varying amounts of protein and either low or normal Pi levels as follows: (1) low Pi/normal protein, (2) low Pi/high (50%) protein, (3) normal Pi/normal protein, and (4) normal Pi/high protein. RESULTS: Intestinal peptide transport activity and PepT1 expression levels were significantly higher in the CKD rats than in sham-operated control ones. Compared with the normal-protein diet, the high-protein diet increased PepT1 expression in the CKD rats. Intestinal dipeptide transport activity and PepT1 protein levels did not increase in the rats fed the low-Pi/high-protein diet. In contrast, intestinal dipeptide transport activity and PepT1 protein expression were markedly increased in the rats fed the normal-Pi/high-protein diet. CONCLUSION: Dietary Pi levels regulate intestinal peptide transport activity through PepT1.

Polysaccharide-K (PSK) may suppress surgical stress-induced metastasis in rat colon cancer.

PURPOSE: We previously demonstrated that hepatic ischemia and reperfusion (I/R) injury increased liver metastasis and cancer growth of RCN-H4 cells. Using a rat model of hepatic I/R-induced liver metastasis, we investigated the metastasis-suppressing effect of polysaccharide-K (PSK), a biological response modifier composed of protein-bound polysaccharide. METHODS: Fischer rats underwent 60 min of 70% partial hepatic ischemia. After 60 min of reperfusion, rat colon adenocarcinoma cells (RCN-H4) were inoculated intrasplenically. PSK was administered orally before I/R, after I/R, or before and after I/R. The weights of metastatic lesions of the liver or the numbers of liver metastatic nodules were determined on day 21. The effect of PSK on angiogenesis was studied by a rat cornea model using RCN-H4 cells or a vascular endothelial growth factor (VEGF)-containing pellet and an in vitro VEGF-induced endothelial cell migration assay. RESULTS: PSK administration significantly (p < 0.05) suppressed the I/R-induced increase in hepatic metastasis of RCN-H4 cells. The suppression of I/R-promoted metastasis was observed irrespective of the timing of administration. Furthermore, PSK significantly suppressed angiogenesis induced by RCN-H4 cells (p < 0.05) and the VEGF pellet (p < 0.01). PSK significantly suppressed the VEGF-induced migration of vascular endothelial cells (p < 0.05). CONCLUSION: PSK may suppress metastasis induced by hepatic I/R. The suppression of angiogenesis by PSK may be one of the mechanisms of the inhibition of hepatic metastasis.

Spherical carbon adsorbent (AST-120) protects deterioration of renal function in chronic kidney disease rats through inhibition of reactive oxygen species production from mitochondria and reduction of serum lipid peroxidation.

BACKGROUND/AIM: An imbalance in renal redox status contributes to progression of renal dysfunction. We investigated the effects of an oral charcoal adsorbent (AST-120) on renal redox status, superoxide production from renal mitochondria, and serum lipid peroxidation using chronic kidney disease (CKD) model rats. METHODS: CKD was induced by 5/6 nephrectomy. CKD rats were divided into 2 groups: controls, and those treated with AST-120 for 20 weeks. We evaluated: (1) renal redox status by in vivo low-frequency electron spin resonance imaging (EPRI); (2) renal superoxide scavenging activity (SSA); (3) superoxide production from renal mitochondria; (4) immunostaining for Cu-Zn superoxide dismutase (SOD), and (5) oxidative stress markers including LDL-negative charge (LDL-CMF), serum lipid peroxide (LPO) and urinary hexanoyl-lysine (HEL). The effect of indoxyl sulfate, a uremic toxin, on mitochondrial superoxide production was also investigated. RESULTS: AST-120 treatment improved renal function, renal SSA, renal mitochondrial superoxide production, renal SOD expression, renal redox status by EPRI, and oxidative stress profiles by LDL-CMF, LPO and urinary HEL. Addition of indoxyl sulfate increased mitochondrial superoxide production and AST-120 also decreased this. CONCLUSIONS: Improvements in the redox status and lipid peroxidation induced by AST-120 may delay the progression of CKD.

Indoxyl sulfate reduces superoxide scavenging activity in the kidneys of normal and uremic rats.

BACKGROUND/AIM: Indoxyl sulfate (IS) is a uremic toxin that accelerates the progression of chronic renal failure (CRF). This study aimed at determining whether IS impairs antioxidative systems (redox status) in the kidney. METHODS: IS was orally administered to normal and subtotally nephrectomized (three fourths and five sixths) rats (CRF rats) for 2 weeks. By use of in vivo and ex vivo electron spin resonance spectroscopy, the kidney redox status was evaluated using carbamoyl-PROXYL as a radical spin probe in living rats, and the kidney superoxide scavenging activity was measured. Immunohistochemistry of superoxide dismutase (SOD) in the kidney was performed. RESULTS: Administration of IS increased serum and kidney levels of IS and serum creatinine and decreased creatinine clearance. CRF rats showed reduced spin reduction rate, prolonged half-life of the spin probe, and reduced superoxide scavenging activity and SOD-positive areas in the kidney as compared with normal rats. Administration of IS further reduced radical spin reduction rate, prolonged half-life of the spin probe, and reduced superoxide scavenging activity and SOD-positive areas in the kidneys. CONCLUSIONS: Administration of IS reduced superoxide scavenging activity in the kidneys of normal and CRF rats. Thus, the nephrotoxicity of IS may be induced by impairing the antioxidative systems in the kidney.

The carboxyl-terminal half region of ADAMTS-1 suppresses both tumorigenicity and experimental tumor metastatic potential.

ADAMTS-1 is an ECM-anchored metalloproteinase with proteoglycan-degrading activity as well as an angiogenesis inhibiting activity. Here, we examined the effects of ADAMTS-1 overexpression on in vivo tumor growth and tumor metastasis. Overexpression of only the C-terminal half region of ADAMTS-1, consisting of TSP type I motifs and the spacer region, suppressed Chinese hamster ovary (CHO) tumor growth in mice. In addition, a significant reduction in tumor metastatic potential was observed in ADAMTS-1-transfected CHO cells in an experimental metastasis assay. Furthermore, deletional analyses revealed that the C-terminal half region of ADAMTS-1 is responsible for its experimental metastasis-inhibitory activity. Our data suggest that the C-terminal half region of ADAMTS-1 has therapeutic potential as an inhibitor of tumor growth and metastasis.

A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity.

A low molecular weight nonpeptide compound, KRH-1636, efficiently blocked replication of various T cell line-tropic (X4) HIV type 1 (HIV-1) in MT-4 cells and peripheral blood mononuclear cells through the inhibition of viral entry and membrane fusion via the CXC chemokine receptor (CXCR)4 coreceptor but not via CC chemokine receptor 5. It also inhibited binding of the CXC chemokine, stromal cell-derived factor 1alpha, to CXCR4 specifically and subsequent signal transduction. KRH-1636 prevented monoclonal antibodies from binding to CXCR4 without down-modulation of the coreceptor. The inhibitory effect against X4 viral replication by KRH-1636 was clearly reproduced in the human peripheral blood lymphocytesevere combined immunodeficiency mouse system. Furthermore, this compound was absorbed into the blood after intraduodenal administration as judged by anti-HIV-1 activity and liquid chromatography MS in the plasma. Thus, KRH-1636 seems to be a promising agent for the treatment of HIV-1 infection.