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 9

TIMP-2 is required for HMGB1- and RIPC-mediated renal protection.

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TIMP-2 is required for HMGB1- and RIPC-mediated renal protection. After ...
After induction of general anesthesia, WT control and TIMP-2–/– mice were pretreated with rHMBG1 or control, and renal IRI was induced by clamping of the renal pedicles for 32 minutes. 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). (B) Serum creatinine levels were measured by a photometric assay (n = 4). (C) Renal tubular injury score was assessed based on histology (n = 4). In an analog set of experiments, WT control and TIMP-2–/– mice received RIPC or sham procedure, and renal IRI was induced by clamping of the renal pedicles for 32 minutes. Twenty-four hours after the surgery, mice were sacrificed. (D) The recruitment of neutrophils (PMNs) into the kidney was analyzed by flow cytometry (n = 4). (E) Serum creatinine levels were measured by a photometric assay (n = 4). (F) Renal tubular injury score was assessed based on histology (n = 4). (G) Cell cycle arrest in renal tubular epithelial cells was analyzed by flow cytometry (n = 4). One-way ANOVA followed by Bonferroni testing was used for statistical analysis; *P < 0.05.