Effection Of Losartan On Renal Function And TNF-α, MCP-1and ICAM-1mRNA In Uric Acid Nephropathy Rat

Objective:To investigate the method of establishing uric acid nephropathy model via a right subcapsular nephrectomy and oxonic acid (OA). To identify the efficacy of losartan on renal protective effect and intervene effect on inflammation in model rats.Methods:All rats underwent a right nephrectomy after baseline measurement of serum uric acid (SUA), blood urea nitrogen (BUN), serum creatinine (SCR), and urinary protein excretion. One week after the operation, a total of31rats were randomly divided into4groups, group A (operation group, n=7), group B (model group, n=10), group C (allopurinol group, n=7) and group D (losartan group, n=7). Group A were administered daily with equal volumes of vehicle (distilled water), group B were administered OA (750mg/kg·d-1) by gastric gavage; group C were administered OA+allopurinol (50mg/kg·d-1); group D rats were administered OA+losartan (30mg/kg·d-1), respectively. Levels of SUA, BUN, SCR and urinary protein excretion were measured every fortnightly. At the8weekend of drugs administration, rats were sacrificed and the kidneys were harvested. Pathological changes of renal tissue were observed by HE and PAS staining. Real-time PCR was used to detect the expression of TNF-a, MCP-1and ICAM-1mRNA in kidney.Results:1. Serum biochemical parameters:At the beginning of study and one week after operation, no significant difference in SUA, BUN and SCR was observed (P>0.05). In operation group rats, a transient increase in SUA, BUN and SCR were observed, but levels approximated to baseline by the end of study. In contrast, model group developed more severe hyperuricemia and renal dysfunction than the operation group (P<0.05). In allopurinol group and losartan group, SUA, BUN and SCR were significant decreased compared with model group (P<0.05). SUA in losartan group was higher than allopurinol group (P<0.05), but BUN and SCR were no statistics significance between the two groups (P>0.05). 2. Urinary protein:excretion After renal ablation, each group rats showed a increase in urinary protein excretion. OA administration rats showed a greater proteinuria, model group rats showed a higher urinary protein excretion compared with the operation rats (P<0.05). Both allopurinol and losartan prevented the increase in proteinuria induced by OA (P<0.05).3. Renal histology:Light microscopy of the kidney exhibited no evidence of uric acid crystal deposition in each group. OA induced a significant increase in glomerular cellularity and mesangial expansion, interstitial with significant infiltration of phlogocytes, tubular atrophy/dilation, protein cast was universal. Both allopurinol and losartan treatment was able to alleviate this alteration.4. Gene levels of TNF-a, MCP-1and ICAM-1in kidney:Real-time PCR indicated that renal gene levels of TNF-a, MCP-1and ICAM-1were significantly increased in the OA administration groups compared with the operation group rats (P<0.05). These gene levels in allopurinol group and losartan administration group were significantly reduced compared with model group (P<0.05), there was no statistics significance between the two treatment groups (P>0.05).Conclusion:1. The method of unite a right subcapsular nephrectomy to oxonic acid administration can establishing a stable uric acid nephropathy model.2. Hyperuricemia may accelerate renal progression via a mechanism linked to high TNF-a, MCP-1and ICAM-1-mediated inflammation disease.3. Losartan may retard the progression of advanced renal dysfunction, and the mechanism may partly due to blocking uric acid-induced renal inflammation.