Interleukin-2-dependent mechanisms are involved in the development of glomerulosclerosis after partial renal ablation in rats

Background: Glomerulosclerosis is a common feature of many end-stage renal diseases. The contribution of cellular immune mechanisms has been implicate d in the development of glomerulosclerosis. We investigated whether the inh ibition of lymphocyte activation influences this process in an established rat model of renal hyperfiltration. Methods: After removal of two-thirds of their respective kidney mass, rats were treated with either tacrolimus (0. 08 mg/kg/day) or vehicle until the end of the study (n = 10/group). The rat s were pair-fed and proteinuria was assessed regularly. Twenty weeks after nephrectomy, creatinine clearance and systemic blood pressure were determin ed, and kidneys were harvested for morphological, immunohistological and PC R analysis. Results: In control animals, renal function started to decline from week 12, as indicated by an elevated proteinuria. Interleukin (IL)-2 a nd IL-2 receptor synthesis was upregulated in control animals and inhibited by tacrolimus treatment. Transforming growth factor-beta (TGF-beta (1)), p latelet-derived growth factor-AA (PDGF-AA) and macrophage chemoattractant p rotein-1 (MCP-1) mRNA levels were upregulated in control animals, but were significantly lower in immunosuppressed hosts. Additionally, tacrolimus tre atment resulted in a significant reduction of proteinuria. Morphological an alysis supported these functional results; glomerular sclerosis, tubular at rophy and intimal proliferation were more pronounced in controls than in th e tacrolimus group. These morphological parameters were accompanied by redu ced infiltration of CD5+ (rat T-cell marker) T cells, ED1+ (rat macrophage marker) macrophages, and less intense staining for laminin and fibronectin. Conclusion: A continuous treatment with tacrolimus an inhibitor of lymphoc yte proliferation - reduced the pace of glomerulosclerosis in the remnant k idney. Copyright (C) 2001 S. Karger AG, Basel.