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

Targeting Sirtuin-1 prolongs murine renal allograft survival and function.

Author information

1
Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
2
Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia and University of Pennsylvania, Philadelphia, PA, USA.
3
Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, PA, USA.
4
Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia and University of Pennsylvania, Philadelphia, PA, USA. Electronic address: beieru@email.chop.edu.

Abstract

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

PMID:
27083279
PMCID:
PMC4834143
DOI:
10.1016/j.kint.2015.12.051
[Indexed for MEDLINE]
Free PMC Article

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