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

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-γ 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.

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