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Published on: December 4, 2010
Protective effects of atorvastatin on chronic allograft nephropathy in rats
Wei Zhang1, Min Liu, Yichao Wu
1Division of Urology and Kidney Transplantation, Nanjing Medical University First Affiliated Hospital, Nanjing, Jiangsu, China. zhangwei@medmail.com.cn
Objective:
Chronic allograft nephropathy (CAN) is the leading cause of late kidney allograft loss. Recent studies have suggested that atorvastatin (ATO) may interact with the acute inflammatory process in the renal interstitium and suppress the proliferation of mesangial cells. We hypothesized that ATO could also inhibit the chronic inflammatory process and prevent the progression of CAN.
Materials And Methods:
Fisher (F344) kidneys were orthotopically transplanted into Lewis rat recipients. Lewis-to-Lewis rat kidney transplantation was served as the syngeneic control (Syn group). Allograft recipients were randomized and treated with cyclosporine A alone (Allo group) or in combination with ATO (15 or 30 mg/kg/d intrgastric, respectively, the low dose treatment group/high dose treatment group [LT/HT] groups). Renal function and the urine protein excretion were analyzed. Animals were sacrificed 20 weeks posttransplantation for histological and immunohistochemical studies, as well as analysis of mRNA levels of cytokines and chemokines.
Results:
Renal function progressively deteriorated and substantial proteinuria developed in the Allo group compared with the Syn group. ATO-treated rats had significantly higher creatinine clearance rate and less amount of proteinuria. Histological examination revealed obvious features of CAN in the Allo group, whereas LT/HT groups demonstrated minimal glomerulosclerosis, interstitial fibrosis, intimal thickening, and tubular atrophy. The numbers of infiltrating mononuclear cells (ED1+, CD8+, and CD68+) decreased markedly, and the intragraft expression of transforming growth factor beta1 (TGF-beta1) and collagen III were also significantly attenuated in the LT/HT groups, as compared with the Allo group. The mRNA levels of proinflammatory cytokines (interleukin-2, interferon-gamma, interleukin-10), chemokines (RANTES, MCP-1), and profibrotic genes (TGF-beta1, collagen III) were significantly down-regulated in ATO-treated rats.
Conclusion:
Atorvastatin showed excellent favorable effects on blocking renal inflammation and fibrosis, and thus, efficiently inhibited the development and progression of CAN, which might improve the long-term survival rate of renal allografts.
Insights
Atorvastatin (ATO) effectively inhibited chronic allograft nephropathy (CAN) in rats by reducing inflammation and fibrosis. This suggests ATO may improve long-term kidney transplant survival.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Chronic allograft nephropathy (CAN) is the primary cause of late kidney transplant failure.
- Atorvastatin (ATO) has shown potential in mitigating acute inflammation and mesangial cell proliferation.
Purpose of the Study:
- To investigate the efficacy of atorvastatin (ATO) in preventing the chronic inflammatory process and progression of chronic allograft nephropathy (CAN).
Main Methods:
- Lewis rats received Fisher kidneys; syngeneic transplants served as controls.
- Allograft recipients were treated with cyclosporine A alone or with ATO (15 or 30 mg/kg/d).
- Renal function, proteinuria, histology, and gene expression of inflammatory markers were assessed at 20 weeks.
Main Results:
- ATO treatment significantly improved renal function and reduced proteinuria compared to controls.
- Histological analysis showed reduced glomerulosclerosis, fibrosis, and interstitial inflammation in ATO-treated groups.
- ATO significantly decreased infiltrating immune cells and downregulated key pro-inflammatory and profibrotic genes.
Conclusions:
- Atorvastatin demonstrated significant protective effects against the development and progression of CAN.
- ATO effectively inhibited renal inflammation and fibrosis, suggesting potential for improved long-term kidney allograft survival.
