title: The heat-shock protein-70-induced renoprotective effect is partially mediated by CD4+ CD25+ Foxp3 + regulatory T cells in ischemia/reperfusion-induced acute kidney injury.
abstract: Recent reports suggest the presence of heat-shock protein (HSP)-reactive T cells with a regulatory phenotype in various inflammatory diseases. To test whether HSP exerts renoprotective effects through regulatory T cells (Tregs), ischemia/reperfusion injury was done with or without heat preconditioning in mice. Splenocytes from heat-preconditioned mice had Treg expansion and a reduced proliferative response upon mitogenic stimulus. T cells from heat-preconditioned mice failed to reconstitute postischemic injury when adoptively transferred to T cell-deficient nu/nu mice in contrast to those from control mice. Tregs were also increased in heat-preconditioned ischemic kidneys. Depleting Tregs before heat preconditioning abolished the renoprotective effect, while adoptive transfer of these cells back into Treg-depleted mice partially restored the beneficial effect of heat preconditioning. Inhibition of HSP70 by quercetin suppressed Treg expansion, as well as renoprotective effects. Transferring Tregs in quercetin-treated heat-preconditioned mice partially restored the beneficial effect of heat preconditioning. The specificity of immune cell HSP70 in renoprotection was confirmed by partial restoration of kidney injury when T cells from HSP70-deficient heat preconditioned mice were adoptively transferred to nu/nu mice. Thus, the renoprotective effect of HSP70 may be partially mediated by a direct immunomodulatory effect through Tregs. Better understanding of immunomodulatory mechanisms of various stress proteins might facilitate discovery of new preventive strategies in acute kidney injury.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea.
authors.forename: Myung-Gyu
authors.initials: MG
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea.
authors.forename: Eun
authors.initials: E
authors.lastname: Jung Cho
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea.
authors.forename: Jae
authors.initials: J
authors.lastname: Won Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Sook Ko
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea.
authors.forename: Hee
authors.initials: H
authors.lastname: Young Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea.
authors.forename: Sang-Kyung
authors.initials: SK
authors.lastname: Jo
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea.
authors.forename: Won Yong
authors.initials: WY
authors.lastname: Cho
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea.
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology*; D000818:Animals; D049109:Cell Proliferation; D004224:Diterpenes; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006358:Hot Temperature; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010641:Phenotype; D015427:Reperfusion Injury / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: D004224:Diterpenes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018840:HSP70 Heat-Shock Proteins; D053645:Interleukin-2 Receptor alpha Subunit; C031049:geranylgeranylacetone