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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 5

Injection of FRCs ameliorates chronic renal injury following repetitive IRI.

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Injection of FRCs ameliorates chronic renal injury following repetitive ...
(A) IR800-NP–labeled FRCs preferentially traffic to KLN draining injured kidney (arrowhead: popliteal LN; white arrow: KLN draining ischemic kidney; blue arrow: KLN draining non-ischemic kidney). (B) Flow cytometric analysis demonstrates that injection of FRCs at time of recurrent IRI leads to increased FRC population in KLN in comparison with injection of vehicle (n = 3/group, mean ± SEM). (C) Light microscopy shows amelioration of kidney injury in mice injected with FRCs at the time of recurrent IRI, as compared with mice injected with vehicle (arrowheads: cast-filled and dilated tubules; arrow: interstitial expansion and hypocellularity). Masson’s trichrome staining shows decreased fibrosis in FRC-treated mice. Scale bars: 75 μm. (D) Substantial declines in fibronectin density and F4/80+ macrophage infiltration of kidney is observed following FRC injection at the time of recurrent IRI. Scale bars: 75 μm. (E) Semiquantitative analysis of the corresponding fluorescent signals in kidney tissue shows significantly lower signals in the FRC-treated group (n = 5–6/group, mean ± SEM). (F) Absolute count of kidney-infiltrating macrophages following IRI, as measured by flow cytometry, confirms a significant drop in macrophage recruitment with FRC treatment (n = 5/group, mean ± SEM). (G) FRC injection prevents architectural changes in KLN following IRI. Scale bars: 500 μm (left) and 200 mm (right). *P < 0.05 by Student’s t test.

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