| ObjectiveMost forms of chronic renal disease progress to end-stage glomerulosclerosis and tubulointerstitial fibrosis. The histologic picture of interstitial renal fibrosis is characterized by tubular atrophy and dilation, interstitial leukocyte infiltration, accumulation of fibroblasts, and increased interstitial matrix deposition. Irrespective and independent of the primary lesion,it is the severity of tubulointerstitial damage and the degree of interstitial leukocyte infiltration that correlates best with the loss of renal function and the risk for progression to end-stage renal disease.The infiltration of leukocytes plays a major role in mediating tubulointerstitial inflammation and fibrosis in chronic renal disease. CC chemokines: regulated on activation of normal T expressed and secreted(RANTES)participate in leukocyte migration and infiltration into inflamed renal tissue. Because RANTES-directed leukocyte migration is mediated by target cell expression of CC chemokine receptor 5(CCR5), this study examined the expression of RANTES and its receptor CCR5 during initiation of tubulointerstitial fibrosis after unilateral ureteral obstruction (UUO) in SD rat,. To explore the effects of retinoic acid(RA) on the expression of RANTES,and investigate the mechanism of RA on tubulointerstitial inflammation and fibrosis of UUOrat.MethodsA total of 135 healthy male SD rats were randomly divided into three groups: sham operation group rats received sham operation without ureteral obstruction;RA treated group and UUO group rats received left ureteral obstruction operation. Then, RA group rats were randomly divided into three subgroup, each subgroup treated with daily subcutaneous injection of Ra with different dosage of 5mg/kg,10mg/kg and 20mg/kg, other two group rats were randomly divided into three subgroup too. each subgroup received same volume vehicle. There were 15 rats in each subgroup,and. Five rats were killed at day 3, 7 and 14 post operation for every group. The percentage of renal tubular lesion and interstitial inflammation, the protein and mRNA expression of RANTES and its receptor CCR5 ,MCP-1,MIP-1α,TGF-β1were assessed and compared..ResultsObstructed kidneys developed hydronephrosis, tubular cell damage, interstitial inflammation, and fibrosis. From days3 to 14, a progressive interstitial influx of macrophages and lymphocytes occurred .In parallel, the protein and mRNA expression of number of TGF-β1 increased from days 3 to 14,mainly expressed in renal tubular and interstitial, rarely in glomeruli. A prominent mRNA expression of RANTES and its receptor CCR5 canbe detected from days 7 to 14. Immunohistochemistry staining studies indicated that RANTES protein mainly expressed in renal tubular and interstitial, rarely in glomeruli. The expression of MCP-1 and MIP-1αincreased progressively from days 7 to 14 too.RA treatment group rats interstitial inflammation and tubular lesion were significantly reduced (P<0.05), RANTES,CCR5,MCP-1,MIP-1α,TGF-β1 protein and mRNA expression were significantly lightened than the same time point rats in UUO group(P<0.01). But nither the histologic nor molecular evidence indicated that there is conspicuous difference among the subgroups treated with different dosages of RA.ConclusionThese data demonstrate an increased expression of RANTES,CCR5,MCP-1,MIP-1αand TGF-β1 at sites of tubulointerstitial damage and progressive fibrosis during unilateral ureteral obstruction that correlates with simultaneous accumulation of interstitial macrophages and T lymphocytes expressing the respective surface receptors CCR5.RA reduced interstitial inflammation and tubular lesion of UUO rat.this role might be through reducing the expression of RANTES,CCR5,MCP-1,MIP-1αand TGF-β1 without dependence of dosage.
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