Gene-Associated Retinoid-Interferon-Induced Mortality 19, Which Is Endogenous Inhibitor of STAT3 Attenuates Tacrolimus-Induced Pancreatic Islet and Renal Injury.

Abstract

Background: Signal transducer and activator of transcription 3 (STAT3) is a key transcription factor of inflammation and fibrosis in kidney. We previously showed that cyclosporine (CsA)-induced renal fibrosis is associated with reduction of gene associated with retinoid interferon induced mortality19 (Grim 19) which is endogenous STAT3 inhibitor. As an extended study, we examined the protective effect of Grim19 in tacrolimus (TAC)-induced pancreatic islet and renal dysfunction and histologic changes using Grim19-overexpressed mice. Methods: Grim19 transgenic mice (TG) in C57BL/6 background were generated by microinjection of a transgene. The presence of the transgene in the founder was confirmed by PCR using genomic DNA extracted from the tail. To induction of TAC-induced injury in mice, TAC (1 mg/kg/day, s.c.) and vehicle (VH, 1 mL/kg/day, s.c.) were daily injected to the 6˜8 week-old TG and wild type (WT) mice for 4 weeks under the 0.01% salt diet. Pancreatic islet and renal function was evaluated using intraperitoneal glucose tolerance test (IPGTT), urine volume, and water intake. Renal fibrosis was observed by Mason trichrome staining in tissue sections. Results: After four weeks treatment of TAC or VH, there was no change of body weight among the all the experimental groups. IPGTT results showed that there was no significant difference of blood glucose level at the 30 min after glucose loading. From 60 min, however, blood glucose level in TAC-treated TG group was significantly decreased compared with TAC-treated WT group. TAC-treated WT group increased 24-h urine volume and water intake, whereas TAC-treated TG group did not. TAC- treated WT groups developed well typical renal tubulointerstitial fibrosis and tubular atrophy in cortex compared with VH group, but TAC-treated TG group showed lower level of fibrosis in renal tissues. Conclusions: Our results demonstrated that Grim-19 improved TAC-induced pancreatic islet and renal injury. These findings provide good evidence that regulation of endogenous STAT3 inhibitor, Grim19 is an important therapeutic target for preventing chronic allograft dysfunction caused by long-tem calcineurin inhibitor treatment in pancreatic islet and renal transplant recipients.