Biology subjects

Crompton, M.

Publications and source records attributed to Crompton, M..

2 recordsLinked to original sources

bioRxiv2025

Matrix Metalloproteinase (MMP) inhibition rescues endothelial glycocalyx damage and reduces neutrophil infiltration in sepsis-associated acute kidney injury

Endothelial glycocalyx (eGlx), a carbohydrate-rich endothelial coat, maintains vascular homeostasis, and its disruption contributes to several vascular diseases. We previously identified matrix metalloproteinase (MMP) 2 and 9-mediated eGlx shedding as a key mechanism in human glomerular endothelial cell (GEnC) damage and kidney dysfunction in diabetes. Here, we sought to determine whether this mechanism contributes to renal and systemic microvascular endothelial cell injury in sepsis-AKI. Sepsis-AKI was induced in mice by lipopolysaccharide (LPS) injection. Confocal microscopy demonstrated glomerular and peritubular eGlx damage, and increased circulating SDC4 demonstrated systemic eGlx shedding. These were associated with enhanced mRNA expression of eGlx components (syndecans 1 and 4) and endothelial inflammatory markers, Intercellular and Vascular Cell Adhesion Molecules (ICAM and VCAM) in the kidney. Additionally, sepsis-AKI markers, serum creatinine and urea, were increased. We found that renal and circulating MMP9, but not MMP2, levels were raised in sepsis-AKI. Moreover, MMP9 staining colocalises with neutrophil, endothelial and mesangial staining in glomeruli in sepsis-AKI. Treatment with MMP2 and 9 inhibitor 1, 1h before LPS injection, prevented glomerular, peritubular and systemic eGlx damage in sepsis-AKI. MMP inhibition also attenuated glomerular leucocyte numbers in sepsis-AKI. We confirmed increased MMP9 activity, shedding of eGlx syndecan 1 and elevated angiopoietin 2 levels, an endothelial damage marker, in sepsis-AKI in humans. Moreover, we used human glomerular endothelial cells (GEnC) in vitro to demonstrate that human sepsis-AKI serum directly damages GEnC eGlx. Our studies confirm that MMP-mediated eGlx damage is a key contributor to renal and systemic microvascular dysfunction in sepsis-AKI and represents a potential therapeutic target for protecting the microvasculature.

cell biology↗

bioRxiv2023

Inhibition of MMP 2 protects the endothelial glycocalyx and improves diastolic function in diabetic cardiomyopathy

The coronary microvascular endothelial glycocalyx (EGlx) is a vital regulator of vascular permeability and EGlx damage contributes to the development of diabetic cardiomyopathy. Matrix metalloproteinases 2 and 9 (MMP2/9) have been identified as key enzymes in the degradation of EGlx components, notably syndecan 4 (SDC4), and are upregulated in diabetes. We tested the hypothesis that inhibition of MMP2/9 can protect the EGlx and improve diastolic function in diabetic cardiomyopathy. Type 1 diabetes was induced in FVB mice by streptozotocin (STZ) injections. Mice were treated with daily injections of the MMP2/9 inhibitor, SB-3CT, for 2 weeks from 7 weeks post STZ. Echocardiography was utilised to assess heart function and lectin staining for the measurement of EGlx depth. Immunolabelling of heart sections for albumin provided an indication of albumin extravasation. A mechanism of EGlx shedding was investigated in vitro in human coronary microvascular endothelial cells treated with TNF- and SB-3CT. Diabetic mice developed diastolic dysfunction from 6 weeks post STZ. MMP2/9 inhibition reversed diastolic dysfunction, EGlx thinning and albumin extravasation in diabetic animals. In vitro, TNF- caused an increase in MMP9 activity and SDC4 shedding from human coronary microvascular endothelial cells. Treatment with SB-3CT reduced MMP9 activity and prevented SDC4 shedding. Knockdown of MMP9 expression prevented TNF- induced SDC4 shedding. This study demonstrates MMP2/9 inhibition as a strategy to protect the EGlx and improve diastolic function in diabetic cardiomyopathy. Our findings suggest new avenues for therapeutic interventions in cardiovascular complications associated with diabetes. Statements and DeclarationsO_ST_ABSCompeting interestsC_ST_ABSThe authors have no competing interests to declare that are relevant to the content of this article.

physiology↗