Transfer of lymphocytes from mice with renal ischemia can induce albuminuria in naive mice: a possible mechanism linking early injury and progressive renal disease?

Abstract

Severe ischemia-reperfusion injury (IRI) predisposes to long-term impairment in kidney function both in patients and experimentally through unknown mechanisms. Given emerging evidence implicating lymphocytes in the pathogenesis of early injury to kidney, liver, and lung after IRI, we hypothesized that kidney IRI would potentially release or expose normally sequestered antigens that would lead to proliferation of antigen-recognizing lymphocytes. This, in turn, would directly participate in progressive kidney injury. To test this hypothesis, we purified splenic lymphocytes from C57BL/6 mice with severe renal IRI or sham operation 6 wk postischemia and transferred these cells to normal mice. Donor mice with IRI had significant fibrosis and cellular inflammation. The recipient mice were followed for 6 or 12 wk. Donor lymphocytes were found to traffic into recipient kidney. Twelve weeks after transfer, kidneys from mice which received IRI-primed lymphocytes exhibited significantly increased urinary albumin excretion compared with lymphocytes from sham mice. Splenic CD3(+), CD4(+), CD3(+)CD25(+), and CD4(+)CD44(+) counts were significantly increased in mice after lymphocyte transfer from IRI mice vs. mice with lymphocytes from sham mice. These data demonstrate that lymphocytes from IRI mice can traffic to recipient kidney and directly mediate albuminuria. These data identify a novel mechanism by which initial kidney injury predisposes to long-term dysfunction and identify lymphocytes as potential therapeutic targets for progressive renal diseases.

Temporary Perioperative Decline of Renal Function Is an Independent Predictor for Chronic Kidney Disease

“…Ischemia and/or reperfusion initiates changes in vascular endothelial cells, tubular epithelial cells, and leukocytes that result in the loss of immune system homeostasis in the kidney with a consequent inflammatory response (16). Animal studies have demonstrated that AKI causes permanent damage to the microvasculature with subsequent abnormalities in kidney structure and function (17). Basile et al (18) demonstrated that recovery from ischemia-reperfusion injury in rats is not complete and that it compromises sodium hemostasis and predisposes to hypertension and secondary renal disease.…”

Human T and Natural Killer Cells Possess a Functional Renin-Angiotensin System

“…Rat leukocytes have been found to secrete angiotensinogen (35), human neutrophils and mast cells were shown to convert AngI to AngII (36), and binding sites were found on human mononuclear cells by using radioactively labeled AngII (37). Although the contribution of monocyte-derived macrophages is established in the pathogenesis of kidney and vascular lesions, other leukocytes, such as NK cells, T cells, and DC, are shown to play crucial roles in renal and vascular diseases (16,38,39). AngII was previously shown to augment murine splenic lymphocyte proliferation by Nataraj et al (40) and others (41), and angiotensin receptor blockers suppress murine T cell antigen responses (42).…”

Ischemia–reperfusion and immediate T cell responses

“…Increased IFN-γ production was not only found in ischemic organs, but also in splenic T cells in the late phase of severe renal IRI without any change in CD4 + and CD8 + T cells numbers [41]. Adoptive transfer of splenic lymphocytes from mice with severe renal IRI induced albuminuria in naïve mice accompanied by migration of donor lymphocytes to recipient kidney and increase of activated and memory T cells in recipient spleen [53]. CD4 + T cells deficient in CD28 or IFN-γ did not restore ischemic injury in nu/nu mice, CD4 KO mice or RAG1 KO mice [40].…”