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.
View: Text | PDF
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

×

Figure 1

Remote ischemic preconditioning (RIPC) protects the murine kidney from IRI by HMGB1 signaling in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Remote ischemic preconditioning (RIPC) protects the murine kidney from I...
After induction of general anesthesia WT mice received either 3 cycles of 5-minute RIPC by inflation of a blood pressure cuff (200 mmHg) positioned to upper leg of the hind limb interrupted by 5-minute reperfusion intervals following cuff deflation. In the control group, the cuff was inflated to 20 mmHg, not resulting in limb ischemia. IRI was induced in WT mice 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 = 5). (B) Serum creatinine levels were measured by a photometric assay (n = 5). (C and D) Exemplary histological images and quantification of histological tubular injury (n = 4–5). Scale bar: 100 µm. (E and F) Plasma HMGB1 levels and urinary HMGB1 levels were analyzed before and after RIPC or control procedure (n = 6). Some mice received either BoxA or a vehicle control before inducing RIPC prior to renal IRI. Twenty-four hours after IRI, mice were sacrificed. (G) The recruitment of neutrophils (PMNs) into the kidney was analyzed by flow cytometry (n = 4-6). (H) Serum creatinine levels were measured by a photometric assay (n = 4-6). Mann-Whitney U test (D) and 1-way ANOVA followed by Bonferroni testing (A, B, and E–H) were used for statistical analysis; *P < 0.05.