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CD4⁺ T Cell-Derived NGAL Modifies the Outcome of Ischemic Acute Kidney Injury.

ABSTRACT: CD4⁺ T cells mediate the pathogenesis of ischemic and nephrotoxic acute kidney injury (AKI). However, the underlying mechanisms of CD4⁺ T cell-mediated pathogenesis are largely unknown. We therefore conducted unbiased RNA-sequencing to discover novel mechanistic pathways of kidney CD4⁺ T cells after ischemia compared with normal mouse kidney. Unexpectedly, the lipocalin-2 (Lcn2) gene, which encodes neutrophil gelatinase-associated lipocalin (NGAL) had the highest fold increase (?60). The NGAL increase in CD4⁺ T cells during AKI was confirmed at the mRNA level with quantitative real-time PCR and at the protein level with ELISA. NGAL is a potential biomarker for the early detection of AKI and has multiple potential biological functions. However, the role of NGAL produced by CD4⁺ T cells is not known. We found that ischemic AKI in NGAL knockout (KO) mice had worse renal outcomes compared with wild-type (WT) mice. Adoptive transfer of NGAL-deficient CD4⁺ T cells from NGAL KO mice into CD4 KO or WT mice led to worse renal function than transfer of WT CD4⁺ T cells. In vitro-simulated ischemia/reperfusion showed that NGAL-deficient CD4⁺ T cells express higher levels of IFN-? mRNA compared with WT CD4⁺ T cells. In vitro differentiation of naive CD4⁺ T cells to Th17, Th1, and Th2 cells led to significant increase in Lcn2 expression. Human kidney CD4⁺ T cell NGAL also increased significantly after ischemia. These results demonstrate an important role for CD4⁺ T cell NGAL as a mechanism by which CD4⁺ T cells mediate AKI and extend the importance of NGAL in AKI beyond diagnostics.

SUBMITTER: Lee SA

PROVIDER: S-EPMC6981061 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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CD4+ T Cell-Derived NGAL Modifies the Outcome of Ischemic Acute Kidney Injury.

Lee Sul A SA Noel Sanjeev S Kurzhagen Johanna T JT Sadasivam Mohanraj M Pierorazio Phillip M PM Arend Lois J LJ Hamad Abdel R AR Rabb Hamid H

Journal of immunology (Baltimore, Md. : 1950) 20191230 3

CD4+ T cells mediate the pathogenesis of ischemic and nephrotoxic acute kidney injury (AKI). However, the underlying mechanisms of CD4+ T cell-mediated pathogenesis are largely unknown. We therefore conducted unbiased RNA-sequencing to discover novel mechanistic pathways of kidney CD4+ T cells after ischemia compared with normal mouse kidney. Unexpectedly, the lipocalin-2 (Lcn2) gene, which encodes neutrophil gelatinase-associated lipocalin (NGAL) had the ...[more]

PMID: 31889023

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Project description:BackgroundRecent researches indicate that the intestinal consequences of renal ischemia reperfusion (IR) would predispose to the translocation of gut-derived endotoxin. Here, we designed experiments to test the hypothesis that the gut-derived endotoxin has a potential role in mediating local inflammatory processes in the acutely injured kidney.MethodsRats were performed sham or renal IR surgery (60?min of bilateral renal ischemia, then 24?h of reperfusion) (n?=?5). The intestinal structural and mucosa permeability were evaluated. Serum endotoxin and bacterial load in liver and mesenteric lymph nodes (MLN) were measured. Separate groups were pretreated with oral norfloxacin 20?mg/kg/day or saline for 4?weeks and divided into sham plus saline, sham plus norfloxacin, renal IR plus saline and renal IR plus norfloxacin group. Serum biochemistry and endotoxin were determined. Kidney pathological changes were scored. Protein or mRNA expression of toll-like receptor 4 (TLR4) and proinflammatory mediators were measured in kidney homogenate.ResultsRenal IR led to marked intestinal integrity disruption and increase in intestinal permeability. These are accompanied by low grade of endotoxemia as well as increased bacterial load in liver and MLN. The group pretreated with norfloxacin showed significant attenuation of the increase in serum urea, ALAT, ASAT and endotoxin. The increased renal protein or mRNA of TLR4 and proinflammatory mediators (IL-6 and MCP-1) in the unpretreated animals was significantly attenuated in the norfloxacin-pretreated animals. However, norfloxacin pretreatment did not produce any protective effects on renal tubular integrity.ConclusionsOur results show for the first time that gut-derived endotoxin, resulting from an increased intestinal permeability after severe renal IR, subsequently amplifies intrarenal inflammatory response by activation renal TLR4 signaling. Our study results do not establish that antibiotic administration was effective in improving the overall renal outcome. However, our findings may be the first step to understanding how to tailor therapies to mitigate intrarenal inflammation in select groups of patients.

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CD4⁺ T Cell-Derived NGAL Modifies the Outcome of Ischemic Acute Kidney Injury.

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CD4<sup>+</sup> T Cell-Derived NGAL Modifies the Outcome of Ischemic Acute Kidney Injury.

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