title: Salt Accelerates Allograft Rejection through Serum- and Glucocorticoid-Regulated Kinase-1-Dependent Inhibition of Regulatory T Cells.
abstract: A high-salt diet (HSD) in humans is linked to a number of complications, including hypertension and cardiovascular events. Whether a HSD affects the immune response in transplantation is unknown. Using a murine transplantation model, we investigated the effect of NaCl on the alloimmune response in vitro and in vivo. Incremental NaCl concentrations in vitro augmented T cell proliferation in the settings of both polyclonal and allospecific stimulation. Feeding a HSD to C57BL/6 wild-type recipients of bm12 allografts led to accelerated cardiac allograft rejection, despite similar mean BP and serum sodium levels in HSD and normal salt diet (NSD) groups. The accelerated rejection was associated with a reduction in the proportion of CD4(+)Foxp3(+) regulatory T cells (Tregs) and a significant decrease in Treg proliferation, leading to an increased ratio of antigen-experienced CD4(+) T cells to Tregs in mice recipients of a HSD compared with mice recipients of a NSD. Because serum- and glucocorticoid-regulated kinase-1 (SGK1) has been proposed as a potential target of salt in immune cells, we fed a HSD to CD4(Cre)SGK1(fl/fl) B6-transplanted recipients and observed abrogation of the deleterious effect of a HSD in the absence of SGK1 on CD4(+) cells. In summary, we show that NaCl negatively affects the regulatory balance of T cells in transplantation and precipitates rejection in an SGK1-dependent manner.
authors.affiliation: Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Transplant Center and Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Kassem
authors.initials: K
authors.lastname: Safa
authors.affiliation: Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ohori
authors.affiliation: Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; School of Biosciences and Biomedical Research Institute, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil;
authors.forename: Thiago J
authors.initials: TJ
authors.lastname: Borges
authors.affiliation: Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Mayuko
authors.initials: M
authors.lastname: Uehara
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Batal
authors.affiliation: Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Tetsunosuke
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Renal Medicine and Transplantation, Royal Free London, National Health Service Foundation Trust, London, United Kingdom; and.
authors.forename: Ciara N
authors.initials: CN
authors.lastname: Magee
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Roger
authors.initials: R
authors.lastname: Belizaire
authors.affiliation: Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Anil
authors.initials: A
authors.lastname: Chandraker
authors.affiliation: Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; lriella@rics.bwh.harvard.edu.
authors.forename: Leonardo V
authors.initials: LV
authors.lastname: Riella
mesh_terms: D000818:Animals; D006084:Graft Rejection / Q000139:chemically induced*; D017874:Immediate-Early Proteins / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000502:physiology*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000502:physiology*; D013997:Time Factors; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D017673:Sodium Chloride, Dietary; D000099184:Serum-Glucocorticoid Regulated Kinases
keywords: Tregs; rejection; salt
references.citation: Mol Cell Biol. 2001 Feb;21(3):952-65
references.pmid: 11154281
references.citation: J Biol Chem. 2003 Feb 21;278(8):5871-82
references.pmid: 12488318
references.citation: Am J Transplant. 2003 Apr;3(4):381-9
references.pmid: 12694059
references.citation: Arq Bras Cardiol. 2003 Mar;80(3):289-300
references.pmid: 12856272
references.citation: J Immunol. 2004 Jun 1;172(11):6539-44
references.pmid: 15153467
references.citation: Transplantation. 1973 Oct;16(4):343-50
references.pmid: 4583148
references.citation: Mol Cell Biol. 1993 Apr;13(4):2031-40
references.pmid: 8455596
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2514-9
references.pmid: 10051674
references.citation: J Immunol. 2005 Mar 15;174(6):3741-8
references.pmid: 15749914
references.citation: J Heart Lung Transplant. 2005 Nov;24(11):1710-20
references.pmid: 16297770
references.citation: Kidney Int. 2012 Nov;82(10):1054-60
references.pmid: 22622502
references.citation: Nature. 2013 Apr 25;496(7446):513-7
references.pmid: 23467085
references.citation: Nature. 2013 Apr 25;496(7446):437-9
references.pmid: 23467087
references.citation: Nature. 2013 Apr 25;496(7446):518-22
references.pmid: 23467095
references.citation: Eur J Immunol. 2013 Jun;43(6):1449-58
references.pmid: 23526606
references.citation: J Clin Invest. 2013 Jul;123(7):2803-15
references.pmid: 23722907
references.citation: Nat Immunol. 2014 May;15(5):457-64
references.pmid: 24705297
references.citation: Clin Transplant. 2006 Jan-Feb;20(1):37-42
references.pmid: 16556151
references.citation: Nat Med. 2009 May;15(5):545-52
references.pmid: 19412173
references.citation: J Hum Hypertens. 2009 Jun;23(6):363-84
references.pmid: 19110538
references.citation: Am J Transplant. 2009 Dec;9(12):2837-44
references.pmid: 19845593
references.citation: Mol Endocrinol. 2010 Feb;24(2):370-80
references.pmid: 19965929
references.citation: Nat Immunol. 2010 Jul;11(7):618-27
references.pmid: 20467422
references.citation: J Exp Med. 2010 Jul 5;207(7):1381-91
references.pmid: 20439537
references.citation: J Exp Med. 2010 Jul 5;207(7):1347-50
references.pmid: 20603315
references.citation: Am J Transplant. 2012 Apr;12(4):846-55
references.pmid: 22300534
references.citation: Nephrol Dial Transplant. 2012 Aug;27(8):3352-9
references.pmid: 22499024