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Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing
Omar H. Maarouf, … , Martina M. McGrath, Reza Abdi
Omar H. Maarouf, … , Martina M. McGrath, Reza Abdi
Published July 12, 2018
Citation Information: JCI Insight. 2018;3(13):e120546. https://doi.org/10.1172/jci.insight.120546.
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Research Article Nephrology

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

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Abstract

The contribution of the kidney-draining lymph node (KLN) to the pathogenesis of ischemia-reperfusion injury (IRI) of the kidney and its subsequent recovery has not been explored in depth. In addition, the mechanism by which repetitive IRI contributes to renal fibrosis remains poorly understood. Herein, we have found that IRI of the kidney is associated with expansion of high endothelial venules (HEVs) and activation of fibroblastic reticular cells (FRCs) in the KLN, as demonstrated by significant expansion in the extracellular matrix. The lymphotoxin α signaling pathway mediates activation of FRCs, and chronic treatment with lymphotoxin β receptor–immunoglobulin fusion protein (LTβr-Ig) resulted in marked alteration of the KLN as well as augmentation of renal fibrosis. Depletion of FRCs reduced T cell activation in the KLN and ameliorated renal injury in acute IRI. Repetitive renal IRI was associated with senescence of FRCs, fibrosis of the KLN, and renal scarring, which were ameliorated by FRC administration. Therefore, our study emphasizes the critical role of FRCs in both the initiation and repair phases of injury following IRI of the kidney.

Authors

Omar H. Maarouf, Mayuko Uehara, Vivek Kasinath, Zhabiz Solhjou, Naima Banouni, Baharak Bahmani, Liwei Jiang, Osman A. Yilmam, Indira Guleria, Scott B. Lovitch, Jane L. Grogan, Paolo Fiorina, Peter T. Sage, Jonathan S. Bromberg, Martina M. McGrath, Reza Abdi

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Figure 3

FRCs play a crucial role in the augmentation of immune activation following IRI.

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FRCs play a crucial role in the augmentation of immune activation follow...
(A) Flow cytometric analysis shows a higher percentage of CD45–PDPN+CD31– FRCs and proliferating (Ki67+) FRCs in KLNs harvested 2 days following IRI from Rag1–/– mice injected with WT T cells than KLNs from those injected with LTα–/– T cells, along with representative flow cytometry plots (gated on CD45– cells) (n = 3–4/group, mean ± SEM). (B) H&E staining (scale bar: 75 μm) of kidney tissue from Rag1–/– mice following IRI demonstrates renal protection upon adoptive T cell transfer from LTα–/– mice, along with (C) lower BUN, as compared with Rag1–/– mice that received T cells from WT mice (n = 3/group, mean ± SEM). (D) Immunofluorescence of KLN shows marked decrease in PDPN+ FRCs in DT-treated CCL19Cre × iDTR mice as compared with untreated WT mice. Paucity in HEV abundance and abrogation of architectural elongation is also shown. Scale bars: 200 μm for PDPN, 100 μm for MECA79. (E) Absolute cell counts of FRCs and HEVs are significantly lower in the KLNs of CCL19Cre × iDTR mice, in comparison with the KLNs from WT mice, as determined by flow cytometric analysis (n = 3/group, mean ± SEM). (F) FRC depletion leads to amelioration in kidney damage after IRI. H&E staining shows less tubular injury in CCL19Cre × iDTR mice, as compared with WT mice. F4/80 staining indicates tissue inflammation is markedly decreased in CCL19Cre × iDTR mice after IRI. LTL identifies proximal tubules. Scale bars: 75 μm. (G) Left panel: Mean cortical thickness of kidneys in FRC-depleted mice was higher than in WT mice following IRI (n = 6/group, mean ± SEM). Right panel: CCL19Cre × iDTR mice are protected from IRI, as indicated by lower BUN (mg/dl) (n = 6/group, mean ± SEM). (H) Left panel: Absolute count of CD4+IFN-γ+ T cells in KLN is significantly lower in CCL19Cre × iDTR mice in comparison with WT mice following IRI. Right panel: Absolute count of CD4+CD44hi T cells in KLN is significantly lower in CCL19Cre × iDTR mice in comparison with WT mice (n = 3–4/group, mean ± SEM). *P < 0.05; **P < 0.01 by Student’s t test.

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