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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Categories: Research Article Nephrology

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

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 1

Activation of fibroblastic reticular cells (FRCs) results in major structural changes in kidney-draining lymph node (KLN) following ischemia-reperfusion injury (IRI) of the kidney.

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Activation of fibroblastic reticular cells (FRCs) results in major struc...
(A) KLN draining ischemic kidney shows loss of T and B cell zone differentiation, as compared with the KLN draining nonischemic kidney (KLN: Ctrl) at 2 days (KLN: IRI(D2)) and 30 days (KLN: IRI(D30)) following IRI. Arrows point to cortical B cell zone, dashed line divides cortical from subcortical T cell zone (arrowheads), while dotted line divides subcortical zone from the medulla containing medullary chordae (inset: asterisk). At both time points, fluorescence reveals increased interstitial extracellular matrix (ECM) in KLN tissue: ER-TR7 and fibronectin (insets show thickened and nodular pattern). Scale bars: 500 μm and 200 μm (inset) for H&E; 200 μm and 100 μm (inset) for ER-TR7 and fibronectin. (B) FRC signal (podoplanin, PDPN) is increased at 2 days (KLN: IRI(D2)) and 30 days (KLN: IRI(D30)) following IRI (inset shows enlarged cytoplasm). Costaining of PDPN and α smooth muscle actin (αSMA) suggests FRC transition in KLN following IRI of the kidney. High endothelial venules (HEVs) stained with MECA79, which labels peripheral node addressin on HEVs, show expansion and elongation 2 days and 30 days following IRI. Scale bars: 200 μm and 100 μm (inset) for PDPN; 100 μm for αSMA+PDPN and MECA79. (C) Following IRI, KLN tissue expresses increased activated FRC gene transcripts, as assessed by qPCR (n = 4/group, mean ± SEM). (D) Flow cytometry of KLNs shows increased CD45–PDPN+CD31– FRC percentage at 2 days following IRI (gated on CD45– cells, representative flow plots) (n = 6/group, mean ± SEM). (E) Flow cytometry of KLNs shows increased CD45–PDPN+CD31–FRC percentage at 30 days following IRI (gated on CD45– cells, representative flow plots) (n = 5/group, mean ± SEM). (F) Flow cytometry of KLNs showed increased percentage of proliferating (Ki-67+) FRCs 2 days and 30 days following IRI in comparison with KLN of nonischemic kidney (n = 3–4/group, mean ± SEM). *P < 0.05; **P < 0.01 by Student’s t test.