The relationship between thiamin, folic acid and cognitive function in a rat model of uremia.

End-stage renal disease is a worldwide health burden, but the pathogenesis of uremia-associated cognitive impairment (CI) is poorly recognized. We hypothesized that uremia brings about deficiency of thiamin and folic acid and causes CI by inducing oxidative stress. Therefore, 24 Sprague-Dawley rats were randomly divided into two groups: a 5/6 nephrectomy group (n = 12) and a sham-operated group (n = 12). The Morris water maze was used to assess the cognitive function eight weeks post-surgery, and serum levels of thiamin, folic acid and homocysteine were detected subsequently. Brain and kidney tissues were collected for pathological examination and 8-Hydroxy-2'-deoxyguanosine (8-OHdG) immunochemistry staining. Results showed that the escape latency on training days 1-2 was longer, and the time in quadrant IV on experimental day 6 was significantly shorter in 5/6 nephrectomy group. Meanwhile, the uremic rats showed decreased thiamin, folic acid and increased homocysteine. We also found the time in quadrant IV was positively correlated with thiamin and folic acid level, while negatively correlated with the blood urea nitrogen and 8-OHdG positive cell proportion. Furthermore, in 5/6 nephrectomy group, the hippocampal neuron count was significantly reduced, and a greater proportion of 8-OHdG positive cells were detected. Pretreating LPS-stimulated rat microglial cells with thiamin or folic acid in vitro alleviated the inflammatory impairment in terms of cell viability and oxidative stress. In summary, we applied a uremic rat model and proved that uremia causes serum thiamin and folic acid deficiency, homocysteine elevation, along with neuron reduction and severe oxidative stress in hippocampus, finally leading to CI.

Morphologic and functional alterations of peritoneum in uremic rats undergoing peritoneal dialysis / 上海第二医科大学学报

Objective To investigate the morphological and functional alterations of peritoneum in uremic rats undergoing peritoneal dialysis(PD). Methods Thirty-five male Wistar rats were randomly divided into control group(sham operated group,n=6),uremia group(5/6 nephrectomy,n=6) and uremia with PD group(n=18).Uremia with PD group was subdivided into three subgroups according to different dialysis period(10 d,4 weeks and 8 weeks,n=6).Omenta were obtained for morphological examination,and peritoneal equilibration tests(PET) were performed to assess the transport function of peritoneal membrane. Results The number of blood vessels per high-power field in the uremia group,uremia with PD group and uremia with PD subgroups(5?3,10?5,17?5 and 19?4) were significantly increased compared with the control group(1?1),and that was much bigger in the uremia with PD group than the uremia group(P

Renoprotective Effect of Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker in Chronic Uremic Rats: Comparison of Early Treatment with Delayed Treatment / 대한신장학회잡지

BACKGROUND: We compared the renoprotective effect of angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) between early treatment and delayed treatment in chronic uremic rats. METHODS: Male Sprague-Dawley rats underwent 5/6 nephrectomy or sham operation (sham) and received no treatment (UC), enalapril (E) 100 mg/L, candesartan cilexetil (C) 10 mg/L or combination of E and C in drinking water. Some rats began to be treated from the next day of 5/6 nephrectomy (early group) and the others began from 12 weeks of 5/6 nephrectomy (delayed group). Blood pressure, renal function, proteinuria, histological changes and renal cortical TGFbeta1 expression were observed for 24 weeks. RESULTS: Blood pressure was significantly lower in E, C or E+C of both early and delayed group than in UC. Particularly blood pressure in E+C of early group was lower than in E or C. In E, C or E+C of both early and delayed group, BUN was lower and creatinine clearance was higher compared with UC. Proteinuria was also significantly lower in E, C or E+C of both early and delayed group compared with UC. In addition, remnant kidney weight in E, C or E+C of early and delayed group was significantly lower compared with UC, representing less renal hypertrophy. On the histological examination, glomerulosclerosis score, interstitial fibrosis score and the number of infiltrated glomerular macrophage were significantly lower in E, C or E+C of both early and delayed group compared with UC. Furthermore, renal cortical TGF-beta1 expression was also lower in E, C or E+C of both early and delayed group compared with UC. CONCLUSION: ACEi and ARB have renoprotective effect biochemically and histologically even though the treatment was delayed until moderate chronic renal failure had occurred.

Effect of Hydroxychloroquine on the Progression of Renal Injury in Chronic Uremic Rats / 대한신장학회잡지

BACKGROUND: Hydroxychloroquine(HCQ) is known to inhibit proinflammatory cytokine production from stimulated mononuclear cells and to have anti-fibrotic effect. The aim of this study was to investigate if HCQ could ameliorate renal injury in chronic uremic rats. METHODS: Using Sprague-Dawley rats, chronic uremia was induced by 5/6 nephrectomy. The rats were divided into 4 groups : normal control rats(NC), uremic control rats(UC) and uremic rats treated with HCQ 10 mg/kg/day(HCQ10) and 20 mg/kg/day (HCQ20). Blood pressure, renal functions, proteinuria and histological changes were followed up for 12 weeks. The glomerular monocyte/macrophage infiltration was evaluated by immunohistochemistry and mRNA expression of MCP-1 and TGF-beta1 was analyzed by RT-PCR. RESULTS: Blood pressure was higher in UC than that in NC from 4 to 12 weeks, and it was lower in HCQ10(from 4 to 12 weeks) and HCQ20(at 4 week) than that in UC. BUN and serum creatinine levels were significantly higher in UC than those in NC from 4 to 12 weeks, and those were significantly decreased in HCQ10 and HCQ20 compared to UC. Creatinine clearance was significantly lower in UC than that in NC from 4 to 12 weeks, and it was increased in HCQ10 and HCQ20 compared to UC. 24 hour proteinurea was significantly increased in UC from 4 to 12 weeks compared to NC, and it was decreased in HCQ10 at 4 and 12 weeks compared to UC. Glomerulosclerosis score was minimal in NC, but was significantly increased in UC from 4 to 12 weeks. It was significantly decreased in HCQ10 and HCQ20 at 8 and 12 weeks compared to UC. Interstitial fibrosis score was also significantly increased in UC from 4 to 12 weeks compared to NC, and it was significantly decreased in HCQ10 and HCQ20 only at 4 weeks compared to UC. The number of glomerular infiltrated monocyte/macrophage in UC was higher than that in NC from 4 weeks, and was peak at 8 weeks. But it was comparable among NC, HCQ10 and HCQ20. MCP-1 mRNA expression were significantly increased in UC compared to NC at 4 and 8 weeks, and it was significantly decreased in HCQ10 at 8 weeks compared to UC. TGF-beta1 mRNA expression were significantly increased in UC compared to NC at 4 and 8 weeks, and it was significantly decreased in HCQ20 at 4 and 8 weeks compared to UC. CONCLUSIONS: Our results suggest that HCQ inhibits MCP-1 and TGF-beta1 mRNA expression in renal cortical tissue and attenuates progression of glomerulosclerosis and interstitial fibrosis in chronic uremic rats, which lead to amelioration of renal function and decrease in proteinuria in chronic uremic rats.