Long-Term Cyclosporine Treatment Reduces the STAT3-Inhibitory Effect by Decreasing GRIM-19 Expression
Convergent Research Consortium for Immunologic Disease, Seoul, Republic of Korea
Transplant Research Center, Seoul, Republic of Korea
Department of Internal Medicine, Division of Nephrology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea
Meeting: 2013 American Transplant Congress
Abstract number: C1208
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). https://atcmeetingabstracts.com/abstract/long-term-cyclosporine-treatment-reduces-the-stat3-inhibitory-effect-by-decreasing-grim-19-expression/. Accessed May 17, 2025.« Back to 2013 American Transplant Congress