| Background and ObjectivesRecently more and more research results support that renin-angiotensin system (RAS) plays an important role in the development of kidney disease. AngiotensinⅡis one of the most active factors in RAS. After binding to receptor, it can produce hemodynamic and nonhemodynamic effects. In kidney disease, nonhemodynamic effects of angiotensinⅡshow that it can enhance the permeability of glomerular basement membrane, promote renal innate cells to proliferate, make inflammatory cells filtrate and conglutinate, meanwhile, it can also impel extracellular matrix of glomeruli to proliferate. So angiotensinⅡcan result in glomerulosclerosis and renal interstitial fibrosis. Toll-like receptors (TLRs) belong to pattern recognition receptors and can recognize pathogen associated molecular patterns. Toll-like receptors play a very important role in immune and inflammatory responses. Recent researches have showed that angiotensinⅡmay induce up-regulation of TLR4, which may accelerate the development of kidney disease. After binding to its receptors, TLR4 can activate nucleus factor-κB (NF-κB) through signal transduction cascade reaction, then promote release of inflammatory factors, such as IL-8. Inflammatory factors can enhance the permeability of glomerular basement membrane and aggravate proteinuria. Angiotensin-converting enzyme inhibitor (ACEI) can protect kidney by nonhemodynamic effects, including reducing the permeability of glomerular basement membrane and the production of extracellular matrix.Therefore the expressions of TLR4, NF-κB and IL-8 in rats with adriamycin nephropathy (ADR), were investigated to explore the mechanism of proteinuria occurrence. In addition, angiotensin-converting enzyme inhibitor (ACEI)-ramipril were used to treat the rats with ADR and the changes of biochemical indicators and glomerulus immunohistochemistry were observed in order to investigate its kidney protective effect and provide firm experimental basis and theoretic evidence.Materials and MethodsForty normal male Wistar rats, six-week old, were bred for one week firstly, and then randomly divided into four groups-normal control group (A), ADR group (B), treated group with regular doses of ramipril (C) and treated group with large doses (D).Rats in group B, C and D were injected adriamycin (6mg/kg) while in group A with equal volume of N.S via caudal veins. Group C and D were administered intragastrically with ramipril by 5mg/(kg.d) and 10mg/(kg.d) respectively after the injections. While group A and B, were administered intragastrically with equal volume N.S everyday. During the period of the experiment, these rats took food and water freely. Five rats were sacrificed in each group in the last day of the 4th and 8th week, respectively. The 24h urinary protein excretion, ALB, CHO and Cys-C in serum were measured. Then renal morphology was observed and the expression level of TLR4, NF-κB and IL-8 were examined by immunohistochemistry.Results1.24UPE in group B, C and D were significantly higher than those in group A either at the 4th week or 8th week (P<0.05), meanwhile,24UPE in group C and D were significantly lower than those in group B (P<0.05).24UPE in group D were significantly lower than those in group C (P<0.05). ALB in group B, C and D were significantly lower than those in group A either at the 4th week or 8th week(P<0.05). Compared with the group B, ALB in group C and D at the 8th week were significantly higher(P<0.05). ALB in group D were significantly higher than those in group C (P<0.05). CHO in group B were higher than those in group A (P<0.05). Compared with the group B, CHO in group C and D did not have statistic difference (P>0.05). Cys-C in group C and D were significantly lower than those in group B (P<0.05). There was no statistic difference between group C and D(P>0.05).2. The organization of kidney in group A was approximately normal and mesangial cells multiplication or glomerular mesangial broadening had not been seen. In the end of the 4th week, we could observe that glomerular mesangial cells and mesangial matrix mildly proliferate, meanwhile inflammatory cells infiltrate in the renal interstitial in group B. In the end of the 8th week, we could observe that glomerular mesangial cells and mesangial matrix moderately proliferate, meanwhile inflammatory cells moderately infiltrate in the renal interstitial in group B. Renal capsule expansion was also observed in group B. However, the pathological changes in group C and D were obviously alleviated.3. The immunohistochemistry results showed that TLR4, NF-κB and IL-8 were weakly expressed in group A. While in group B they were up-regulated(P<0.05) from the 4th week to the 8th week. However, expressions of TLR4, NF-κB and IL-8 in group C and D were lower than those in group B(P<0.05). Expressions of TLR4, NF-κB and IL-8 in group D were lower than those in group C (P<0.05).Conclusions1. In rats with adriamycin nephropathy, expressions of TLR4, NF-κB and IL-8 were up-regulated, suggesting that maybe up-regulation of TLR4, NF-κB and IL-8 is an important reason for the production of proteinuria.2. The mechanism for proteinuria reduction and kidney protection by ramipril in rats with adriamycin nephropathy maybe related to down-regulation of TLR4, NF-κB and IL-8.
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