Remote ischemic preconditioning causes transient cell cycle arrest and renal protection by a NF-κB–dependent Sema5B pathway
Jan Rossaint, Melanie Meersch, Katharina Thomas, Sina Mersmann, Martin Lehmann, Jennifer Skupski, Tobias Tekath, Peter Rosenberger, John A. Kellum, Hermann Pavenstädt, Alexander Zarbock
Jan Rossaint, Melanie Meersch, Katharina Thomas, Sina Mersmann, Martin Lehmann, Jennifer Skupski, Tobias Tekath, Peter Rosenberger, John A. Kellum, Hermann Pavenstädt, Alexander Zarbock
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Research Article Immunology Nephrology

Remote ischemic preconditioning causes transient cell cycle arrest and renal protection by a NF-κB–dependent Sema5B pathway

Abstract

Acute kidney injury increases morbidity and mortality, and previous studies have shown that remote ischemic preconditioning (RIPC) reduces the risk of acute kidney injury after cardiac surgery. RIPC increases urinary high mobility group box protein-1 (HMGB1) levels in patients, and this correlates with kidney protection. Here, we show that RIPC reduces renal ischemia-reperfusion injury and improves kidney function in mice. Mechanistically, RIPC increases HMGB1 levels in the plasma and urine, and HMGB1 binds to TLR4 on renal tubular epithelial cells, inducing transcriptomic modulation of renal tubular epithelial cells and providing renal protection, whereas TLR4 activation on nonrenal cells was shown to contribute to renal injury. This protection is mediated by activation of induction of AMPKα and NF-κB; this induction contributes to the upregulation of Sema5b, which triggers a transient, protective G1 cell cycle arrest. In cardiac surgery patients at high risk for postoperative acute kidney injury, increased HMGB1 and Sema5b levels after RIPC were associated with renal protection after surgery. The results may help to develop future clinical treatment options for acute kidney injury.

Authors

Jan Rossaint, Melanie Meersch, Katharina Thomas, Sina Mersmann, Martin Lehmann, Jennifer Skupski, Tobias Tekath, Peter Rosenberger, John A. Kellum, Hermann Pavenstädt, Alexander Zarbock

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Figure 7

Sema5b upregulation is involved in HMBG1-medieated renal protection.

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Sema5b upregulation is involved in HMBG1-medieated renal protection. (A)...
(A) Isolated murine renal tubular epithelial cells were lysed, and Sema5b and p38 (as a loading control) was detected by Western blotting (exemplary blot from n = 4 independent experiments). (B) Murine renal tubular epithelial cells and neutrophils were isolated from WT mice 4 hours after sham or RIPC application, and Sema5b expression was analyzed by qPCR (n = 4). (C) Murine renal tubular epithelial cells were isolated from WT or TLR4/Ksp-Cre mice 4 hours after injection of rHMGB1 and/or a NF-κB inhibitor (Bay-117082, 10 mg/kg i.p.), and Sema5b expression was analyzed by qPCR (n = 4). (D) Isolated murine renal tubular epithelial cells were isolated from WT mice 4 hours after RIPC procedure, and Sema5b expression was detected by qPCR (n = 4). (E) Isolated WT or Sema5B-KD murine renal tubular epithelial cells were treated with control or HMGB1 (0.1 μg/mL) in vitro for 24 hours. (F and G) Cell cycle analysis was performed by measuring cellular DNA content by flow cytometry, and TIMP-2 (F) and IGFBP7 (G) released into the supernatant were analyzed by ELISA (n = 4–6). (H) Isolated WT or Sema5b-KD murine renal tubular epithelial cells were treated with control or PlexinA1 in vitro for 24 hours. (I and J) Cell cycle analysis was performed by measuring cellular DNA content by flow cytometry and TIMP-2 (I) and IGFBP7 (J) released into the supernatant were analyzed by ELISA (n = 4–6). One-way ANOVA followed by Bonferroni testing was used for statistical analysis; *P < 0.05.