Remote ischemic preconditioning causes transient cell cycle arrest and renal protection by a NF-κB–dependent Sema5B pathway
Jan Rossaint, … , Hermann Pavenstädt, Alexander Zarbock
Jan Rossaint, … , Hermann Pavenstädt, Alexander Zarbock
Published June 21, 2022
Citation Information: JCI Insight. 2022;7(14):e158523. https://doi.org/10.1172/jci.insight.158523.
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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 3

Administration of HMGB1 protects from AKI, and blocking HMGB1 abrogates the protective effect of RIPC.

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Administration of HMGB1 protects from AKI, and blocking HMGB1 abrogates ...
After induction of general anesthesia, renal IRI was induced in WT mice by clamping of the renal pedicles for 32 minutes. Some groups received rHMGB1 (0.3, 3, or 30g/mouse) or rHMGB1 plus a TLR4 inhibitor before the induction of renal IRI. Twenty-four hours after the surgery, mice were sacrificed. (A) The recruitment of neutrophils (PMNs) into the kidney was analyzed by flow cytometry (n = 4–6). (B) Serum creatinine levels were measured by a photometric assay (n = 4–6). In additional experiments, IRI was induced in WT control and TLR4fl/fl/Ksp-Cre+/T mice, which did or did not receive RIPC prior to IRI induction by clamping of the renal pedicles for 32 minutes. Twenty-four hours after the surgery, mice were sacrificed. (C) The recruitment of neutrophils (PMNs) into the kidney was analyzed by flow cytometry (n = 4). (D) Serum creatinine levels were measured by a photometric assay (n = 4). (E and F) The biomarkers TIMP-2 and IGFBP7 were measured in urine samples after RIPC application (E) and 24 hours after IRI (F). (G and H) Exemplary histological images and quantification of histological tubular injury (n = 4). Scale bar: 100 µm. (I–K) The levels of the chemokines CXCL1 (I), CXCL2 (J), and IL-6 (K) in kidney tissue homogenisates were analyzed by ELISAs (n = 4). One-way ANOVA followed by Bonferroni testing was used for statistical analysis; *P < 0.05.