Decreased Capacity of Immune Cells to Cause Tissue Injury Mediates Kidney Ischemic Preconditioning

Abstract

Ischemic preconditioning (IP) is a well-established phenomenon, and the underlying mechanisms of IP are thought to involve adaptive changes within the injured tissue. Because one of the main functions of immune cells is to harbor memory, we hypothesized that circulating immune cells could mediate IP by responding to an initial ischemia reperfusion injury (IRI) and then mediate decreased injury after a second IRI event. C57BL/6 mice underwent 30 min of bilateral renal clamping or sham operation. At 5 days after ischemia, purified leukocytes from spleen were adoptively transferred into T cell-deficient (nu/nu) mice. After 1 wk, these mice underwent 30 min of renal IRI. The nu/nu mice receiving leukocytes from ischemic wild-type mice had significantly reduced renal injury compared with nu/nu mice receiving leukocytes from sham-operated, wild-type mice. Infiltration of neutrophil and macrophage in postischemic kidney did not correlate with the protection. No difference in kidney C3d or IgG deposition was detected between groups. Given that inducible NO synthase (iNOS) has been implicated in IP, leukocytes from ischemic or sham-operated, iNOS-deficient mice were transferred into nu/nu mice. Effects similar to those of wild-type transfer of ischemic leukocytes were demonstrated; thus, iNOS was not mediating the IP effect of leukocytes. This is the first evidence that immune cells are primed after renal IRI and thereby lose the capacity to cause kidney injury during a second episode of IRI. This finding may also be relevant for elucidating the mechanisms underlying cross-talk between injured kidney and distant organs.

Phenotypic and Functional Characterization of Kidney-Infiltrating Lymphocytes in Renal Ischemia Reperfusion Injury

“…These data are consistent with previous data in kidney IRI (13) and liver IRI (14) that lymphocytes could play a deleterious or protective role in IRI. Furthermore, recent data support a protective role in splenic lymphocytes when harvested 5 days after kidney IRI to confer an "ischemic preconditioning"-like protection when transferred to wild-type mice when they undergo IRI (35). The current data do not identify which particular cell type could be responsible for this effect or whether either earlier or later time point KMNC have a different effect.…”

Hepcidin Mitigates Renal Ischemia-Reperfusion Injury by Modulating Systemic Iron Homeostasis

“…This is supported by our finding that lipid peroxidation (a marker of iron-mediated injury/ferroptosis) is reduced in hepcidin-treated mice subjected to IRI. 52 Previous studies have suggested an important role of the spleen [43][44][45] and liver 53 in the pathophysiology of renal IRI. We demonstrate that IRI induces hepatosplenic iron export, which likely contributes to the pathogenesis of renal IRI.…”

“…[43][44][45] Splenic macrophages play a sentinel role in systemic iron homeostasis. Because splenic iron content decreases after renal IRI, we examined the expression of ferroportin in splenic macrophages.…”

Ischemia–reperfusion and immediate T cell responses

“…These data suggest infiltrating T cells have a complex role in the different phases of IRI. The protective role of splenic lymphocytes 5 days after renal IRI was also demonstrated when transferred to wild type mice with IRI [63]. However, the particular cell type responsible for the aforementioned protective effects has not been identified yet.…”