Targeting sirtuin-1 improves murine renal allograft survival and function (TRAN3P.901)

Abstract Pharmacologic inhibition of sirtuin-1 (Sirt1) augments suppressive functions of Foxp3+ regulatory T cells (Treg) and prolongs murine cardiac allograft survival. We investigated if Sirt1 targeting produced longer allograft function and allograft-dependent survival in a MHC-mismatched renal transplant model. After transplantation of BALB/c kindey allografts into C57Bl/6 wild type or fl-Sirt1/CD4cre recipients, native kidneys were removed three days post-operatively. We followed the mice for survival, and allograft function by weekly serum electrolyte and renal function (BUN, creatinine), as well as hematocrit. We observed, that loss of Sirt1 in T cells led to prolonged median renal allograft-dependent survival from 14 days (IQR: 11-91.25) to 143 days (IQR: 27-147) in wild type controls vs. fl-Sirt1/CD4cre recipients (Mantel-Cox, p<0.0004). In addition, by comparing mice that survived until 13 weeks, loss of Sirt1 in the recipient’s T cells led to improved renal allograft function, with 34.2 ±20 vs. 90.8 ±37.6 mg/dL BUN (p<0.001), and lower creatinine 0.33 ±0.14 vs. 0.61 ±0.3 mg/dL (p<0.001) in fl-Sirt1/CD4cre vs. wild type control mice, respectively. Long-term surviving fl-Sirt1/CD4cre renal transplant recipients (>100 days) became tolerant to antigen re-challenge with a BALB/c, but rejected third-party C3H cardiac allografts. In conclusion, deletion of Sirt1 in T cells is effective at prolonging allograft function and allograft-dependent survival.