Targeting Sirtuin-1 prolongs murine renal allograft survival and function

Kidney Int. 2016 May;89(5):1016-1026. doi: 10.1016/j.kint.2015.12.051. Epub 2016 Mar 16.


Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3(+) T-regulatory cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3(+) T-regulatory suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1(fl/fl)CD4(cre)) or mice treated with a Sirtuin-1-specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1(fl/fl)CD4(cre) recipients showed markedly longer survival and improved kidney function. Sirt1(fl/fl)CD4(cre) recipients exhibited donor-specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell-mediated rejection. However, effects on non-T cells that could adversely affect allograft survival and function merit consideration.

Keywords: acute rejection; chronic allograft nephropathy; tolerance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allografts
  • Animals
  • Carbazoles / pharmacology*
  • Female
  • Graft Rejection / enzymology
  • Graft Rejection / immunology
  • Graft Rejection / physiopathology
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Immunosuppressive Agents / pharmacology*
  • Kidney / drug effects*
  • Kidney / enzymology
  • Kidney / immunology
  • Kidney / physiopathology
  • Kidney Transplantation / adverse effects*
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Sirtuin 1 / antagonists & inhibitors*
  • Sirtuin 1 / deficiency
  • Sirtuin 1 / genetics
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / enzymology
  • T-Lymphocytes, Regulatory / immunology
  • Time Factors
  • Transplantation Tolerance / drug effects


  • 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
  • Carbazoles
  • Histone Deacetylase Inhibitors
  • Immunosuppressive Agents
  • Sirt1 protein, mouse
  • Sirtuin 1