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 HMGB1 (high mobility group box protein-1) levels in patients which 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 Toll-like receptor 4 (TLR4) on renal tubular epithelial cells, inducing transcriptomic modulation of renal tubular epithelial cells and providing renal protection, whereas TLR4 activation on non-renal cells was shown to contribute to renal injury. This protection is mediated by activation of induction of AMPK⍺ and NF-kB, which induces the upregulation of Sema5b that 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.

NephroCheck at 10: addressing unmet needs in AKI diagnosis and risk stratification

“…In murine unilateral ureteric obstruction, kidney Timp2 mRNA did not increase until aft the chronic phase (after 14 days following IRI), while tubular TIMP2 remained unchanged or increased after 48 h [ 36 , 37 ]. These findings are consistent with a scenario in which high urinary [TIMP2]*[IGFBP7] may to some extent reflect preexistent kidney injury, a hypothesis supported by a recent manuscript in CKJ that presents human kidney biopsy data [ 38 ]. In this regard, CKD is a key risk factor for AKI and a decreased eGFR is a late consequence (and diagnostic criterion) of CKD.…”

“…[TIMP2]*[IGFBP7] are thought to be markers of tubular cell cycle arrest. However, cell cycle arrest may have diverse roles in AKI [ 38 , 39 ]. On one hand, a transient, protective G1 cell cycle arrest may be triggered by ischemic preconditioning and contribute to kidney protection [ 38 ].…”

IKK1 aggravates ischemia–reperfusion kidney injury by promoting the differentiation of effector T cells

“…The activation of NFκB plays a pivotal role in renal injury after IRI as we and others have shown previously [ 9 , 15 , 30 ]. NFκB is activated both in renal parenchymal and in infiltrating inflammatory cells after IRI-induction [ 31 – 35 ].…”

Research hotspots and frontiers of preconditioning in cerebral ischemia: A bibliometric analysis

“…RIPC successfully induces ischemic tolerance not only in the brain, but also in the heart [ 151 ], kidneys [ 152 ], lungs [ 153 ], and liver [ 154 ], which seems to suggest that repeated ischemic preconditioning of one artery may have induced ischemic tolerance throughout the body. How does this protective effect extend from local to other areas?…”