Increased R‐spondin 3 contributes to aerobic exercise‐induced protection against renal vascular endothelial hyperpermeability and acute kidney injury

Abstract

AimExercise training exerts protective effects against sepsis‐associated multiple organ dysfunction. This study aimed to investigate whether aerobic exercise protected against sepsis‐associated acute kidney injury (AKI) via modulating R‐spondin 3 (RSPO3) expression.MethodsTo investigate the effects of aerobic exercise on lipopolysaccharide (LPS)‐induced AKI, LPS (20 mg/kg) was intraperitoneally injected after six weeks of treadmill training. To investigate the role of RSPO3 in LPS‐induced AKI, wild‐type (WT) or inducible endothelial cell‐specific RSPO3 knockout (RSPO3EC−/−) mice were intraperitoneally injected with 12 mg/kg LPS. RSPO3 was intraperitoneally injected 30 min before LPS treatment.ResultsAerobic exercise‐trained mice were more resistant to LPS‐induced body weight loss and hypothermia and had a significant higher survival rate than sedentary mice exposed to LPS. Exercise training restored the LPS‐induced decreases in serum and renal RSPO3 levels. Exercise or RSPO3 attenuated, whereas inducible endothelial cell‐specific RSPO3 knockout exacerbated LPS‐induced renal glycocalyx loss, endothelial hyperpermeability, inflammation, and AKI. Bioinformatics analysis results revealed significant increases in the expression of matrix metalloproteinases (MMPs) in kidney tissues of mice exposed to sepsis or endotoxaemia, which was validated in renal tissue from LPS‐exposed mice and LPS‐treated human microvascular endothelial cells (HMVECs). Both RSPO3 and MMPs inhibitor restored LPS‐induced downregulation of tight junction protein, adherens junction protein, and glycocalyx components, thus ameliorating LPS‐induced endothelial leakage. Exercise or RSPO3 reversed LPS‐induced upregulation of MMPs in renal tissues.ConclusionIncreased renal expression of RSPO3 contributes to aerobic exercise‐induced protection against LPS‐induced renal endothelial hyperpermeability and AKI by suppressing MMPs‐mediated disruption of glycocalyx and tight and adherens junctions.

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“…The researchers conclude that an Increased renal expression of RSPO3 contributes to aerobic exercise-induced protection against LPS-induced renal endothelial hyperpermeability and AKI by suppressing MMPs-mediated disruption of glycocalyx and tight and adherens junctions. 3 Since the authors did not investigate humans the clinical relevance to humans of those findings are yet to be determined.…”

“…In sepsis, the kidneys can be significantly impacted, leading to acute kidney injury (AKI) due to the body's response to infection, impaired blood flow, and the release of inflammatory mediators. Exercise has been suggested to have an protective effect in sepsis‐associated organ dysfunction 3 . In a study by Xu et al 3 .…”

“…Exercise has been suggested to have an protective effect in sepsis‐associated organ dysfunction 3 . In a study by Xu et al 3 . the authors wanted to test that this effect is related to R‐spondin 3.…”

“…The authors find that aerobic exercise‐trained mice were more resistant to LPS‐induced body weight loss and hypothermia and had a significant higher survival rate than sedentary mice exposed to LPS. The researchers conclude that an Increased renal expression of RSPO3 contributes to aerobic exercise‐induced protection against LPS‐induced renal endothelial hyperpermeability and AKI by suppressing MMPs‐mediated disruption of glycocalyx and tight and adherens junctions 3 . Since the authors did not investigate humans the clinical relevance to humans of those findings are yet to be determined.…”

“…Exercise has been suggested to have an protective effect in sepsis-associated organ dysfunction. 3 In a study by Xu et al 3 the authors wanted to test that this effect is related to R-spondin 3. To this end the authors used inducible endothelial cell-specific RSPO3 knock out mice in a LPS-induced acute kidney injury model in trained and untrained mice.…”