Febuxostat Attenuates Renal Damage besides Exerting Hypouricemic Effect in Streptozotocin-Induced Diabetic Rats.

Aim. In this study, we aimed to investigate the effects of febuxostat, a novel inhibitor of xanthine oxidase (XO), on renal damage in streptozotocin- (STZ-) induced diabetic rats. Methods. Diabetes was induced by the intraperitoneal injection of STZ in male Sprague-Dawley rats. Sham-injected rats served as controls. The control and diabetic rats were treated with and without febuxostat for 8 weeks, respectively. Fasting blood and 24-h urine samples were collected every 4 weeks. Rat livers were extracted for detecting gene expression, content, and bioactivity of XO. Results. Diabetic rats showed significantly increased serum uric acid (SUA), serum creatinine (SCr), and urea nitrogen (BUN) levels. Daily urinary albumin (UAE), uric acid (UUA), and creatinine (UCr) excretion were also significantly increased in these rats. In diabetic rats, at week 8, febuxostat decreased SUA by 18.9%, while UAA was increased by 52.0%. However, UCr and urinary urea nitrogen (UUN) levels remained unchanged, while SCr and BUN levels decreased by >30% in these rats. Although hepatic gene expression, content, and activity of XO increased significantly in diabetic rats, febuxostat only slightly decreased its content. Conclusions. Febuxostat significantly attenuated renal damage in STZ-induced diabetic rats in addition to exerting hypouricemic effect.

Low protein diet inhibits uric acid synthesis and attenuates renal damage in streptozotocin-induced diabetic rats.

AIM: Several studies indicated that hyperuricemia may link to the worsening of diabetic nephropathy (DN). Meanwhile, low protein diet (LPD) retards exacerbation of renal damage in chronic kidney disease. We then assessed whether LPD influences uric acid metabolism and benefits the progression of DN in streptozotocin- (STZ-) induced diabetic rats. METHODS: STZ-induced and control rats were both fed with LPD (5%) and normal protein diet (18%), respectively, for 12 weeks. Vital signs, blood and urinary samples for UA metabolism were taken and analyzed every 3 weeks. Kidneys were removed at the end of the experiment. RESULTS: Diabetic rats developed into constantly high levels of serum UA (SUA), creatinine (SCr) and 24 h amounts of urinary albumin excretion (UAE), creatinine (UCr), urea nitrogen (UUN), and uric acid (UUA). LPD significantly decreased SUA, UAE, and blood glucose, yet left SCr, UCr, and UUN unchanged. A stepwise regression showed that high UUA is an independent risk factor for DN. LPD remarkably ameliorated degrees of enlarged glomeruli, proliferated mesangial cells, and hyaline-degenerated tubular epithelial cells in diabetic rats. Expression of TNF-α in tubulointerstitium significantly decreased in LPD-fed diabetic rats. CONCLUSION: LPD inhibits endogenous uric acid synthesis and might accordingly attenuate renal damage in STZ-induced diabetic rats.

Increased plasma adiponectin closely associates with vascular endothelial dysfunction in type 2 diabetic patients with diabetic nephropathy.

Several studies found that adiponectin, an adipokine withstands atherosclerosis in vivo, is significantly increased in subjects with diabetic nephropathy (DN), but its clinical meaning remains unclear. For its structural similarity to complement C1q and collagen, we performed this study to explore the relationship between adiponectin and the vascular endothelial function alterations in DN patients. 50 type 2 diabetic patients without clinical cardiovascular complications were assigned to control group, microalbuminuria group (Micro-MA), and macroalbuminuria group (Macro-MA) according to the Mogensen's criteria. Plasma adiponectin and soluble vascular cell adhesion molecule-1 (sVCAM-1) were detected. Flow-mediated dilatation (FMD), nitroglycerin-induced dilatation (NID) and cardiologic parameters were measured by ultrasound cardiogram. Plasma adiponectin level was significantly and gradually increased in agreement with the amount of urine albumin excretion. sVCAM-1 was higher in Micro-MA and Macro-MA patients than in the controls, but it was comparable between the former 2 groups. FMD and NID were both remarkably decreased in Macro-MA group compared with Micro-MA and control group. For the whole subjects, plasma adiponectin was negatively related to FMD (r=-0.397, P<0.01) and NID (r=-0.413, P<0.01). These results suggest that increased plasma adiponectin may predict co-existing vascular endothelial dysfunction in DN patients.

[Effects of angiotensin II type 1 receptor blocker on triglyceride metabolism in the liver: experiment with Zucker fatty rats].

OBJECTIVE: To investigate the effects of angiotensin receptor blocker (ARB) on triglyceride (TG) medoxomil metabolism and mechanism thereof. METHODS: Zucker fatty (ZF) rats and Zucker lean (ZL) rats were fed with water containing 0.01% olmesartan , a highly specific ARB for 4 weeks. Frequently sampled intravenous glucose tolerance test was conducted to calculate the area under the glucose (AUCG), insulin sensitivity index (SI), glucose effectiveness (SG), Blood glucose, TC, TG, nonesterified fatty acid (NEFA), and HDL-C were measured with standard assay kit. Triton WR-1339 technique was used to detect the TG secretion rate (TGSR). After TGSR and FS-IVGTT the levers were collected. The total cholesterol (TC) of the liver was detected, and Sudan IV staining was used to detect the triglyceride in the liver. Enzymatic method was used to measure the TG and TC in the liver extract. RESULTS: The blood pressure of both groups was lowered in both strains to the same extent after olmesartan taking. The SI value of the ZF rats was (0.31 +/- 0.22) microU x ml(-1) x min(-1) x 10(-4) significantly lower than that of the ZL rats (3.54 +/- 0.30) microU x ml(-1) x min(-1) x 10(-4), P < 0.01). Bergman's minimal model showed that the SG value of the ZF rats was (1.35 +/- 0.51) min(-1) x 10(-2), significantly lower than that of the ZL rats (3.40 +/- 0.14 min(-1) x 10(-2), P < 0.01). The plasma glucose levels of the ZF rats was (11.4 +/- 2.6) mmol/L, significantly higher than that of the L rats [(9.2 +/- 0.6) mmol/L, P < 0.01]. Olmesartan treatment substantially elevated both the baseline SI and SG levels of the ZF rats. The TG of the ZF rats was 6 times as high as that of the ZL rats. The plasma NEFA level after olmesartan treatment of the ZF rats was Olmesartan treatment, significantly lower than that before treatment [(2.70 +/- 0.69) mEq/L, P < 0.01], however, the plasma TG level of the ZF rats after the treatment was not significantly different from that before treatment (P > 0.05). The TGSR rate of the ZF rats was almost 6 times that of the ZL rats. Olmesartan treatment lowered the TG overproduction by half (0.56 +/- 0.08) mg x min(-1) x 100 g(-1) BW vs (0.30 +/- 0.07) mg x min(-1) x 100 g(-1) BW, (P < 0.01). The liver TG content of the ZF rats was 10 times that of the ZL rats. Olmesartan treatment lowered the liver TG content from (22.7 +/- 4.2) mg/g to (12.8 +/- 1.7) mg/g (P < 0.01) without affecting the cholesterol content. Pathology showed that the fatty liver developed in the ZF rats was significantly ameliorated by olmesartan treatment. Olmesartan treatment had no significant effect on TG metabolism or insulin sensitivity in the ZL rats. CONCLUSION: ARB improves the overproduction and accumulation of TG in the liver associated with insulin resistance, and does so through mechanisms independent of its hypotensive action.