Background: Kidney fibrosis, a typical characteristic of chronic cyclosporine (CsA) nephropathy is associated with activation of STAT3 (signal transducer and activator of transcription 3). Recently, GRIM-19, a gene associated with retinoid interferon induced mortality, as an interacting protein of STAT3 by yeast two-hybrid screening has been identified. Here, we examined the expression of GRIM-19 and STAT3 on CsA-induced renal interstitial fibrosis in an experimental mouse model.
Methods: Mice were treated with three dosage of CsA (7.5, 15, 30 mg/kg/day, s.c.) or olive oil (VH group, 1ml/kg, s.c.) under 0.01% salt diet for 4 weeks. CsA-induced renal interstitial fibrosis was evaluated by quantitative analysis of Mason trichrome stained tissue. The expression of phosphorylation of STAT3 (Tyr 705, p-STAT3) and GRIM-19 was evaluated with immunoblot analysis.
Results: 7.5 or 15 mg/kg of CsA treatment produced fibrosis as a minimal level, whereas 30 mg/kg of CsA treatment showed typical tubulointerstitial fibrosis in the cortex compared with the other groups (5 ± 0.3% in the CsA7.5 group, 8 ± 2% in the CsA15 group, and 19 ± 2% in the CsA30 group vs. 0 ± 0% in the VH group). Results showed that there were no difference in the expression of p-STAT3 and GRIM-19 in the CsA7.5 group compared with the VH group. Both subunits of p-STAT3 were decreased in a 1.2-fold whereas GRIM-19 expression was increased in a 1.2-fold in the CsA15 group (Α subunit: 84 ± 3 vs. 100 ± 10; Β subunit: 125 ± 7 vs. 139 ± 5 ; GRIM-19: 119 ± 5 vs. 100 ± 4, P < 0.05 vs. VH group). However, CsA30 treatment significantly increased the expression of p-STAT3, but decreased GRIM-19 expression compared with the VH group (Α subunit: 132 ± 7 vs. 100 ± 10; Β subunit: 207 ± 10 vs. 139 ± 5; GRIM-19: 71 ± 5 vs. 100 ± 4, P < 0.05 vs. VH group).
Conclusion: These results suggest that GRIM-19 suppresses the phosphorylation of STAT3 until CsA15 treatment, result in limited level of fibrosis induction. However, CsA30 treatment reduced the expression of GRIM-19, which means activation of STAT3. Our findngs suggest that long-term CsA treatment decrease STAT3-inhibitory action of GRIM-19 and it may contribute the progression of chronic renal fibrosis.
To cite this abstract in AMA style:Lim S, Doh K, Jin L, Piao S, Heo S, Chung B, Yang C. Long-Term Cyclosporine Treatment Reduces the STAT3-Inhibitory Effect by Decreasing GRIM-19 Expression [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/long-term-cyclosporine-treatment-reduces-the-stat3-inhibitory-effect-by-decreasing-grim-19-expression/. Accessed September 23, 2017.
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