Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx

Crompton, Michael; Ferguson, Joanne; Ramnath, RainaD; Onions, Karen L.; Ogier, Anna S.; Gamez, Monica; Down, Colin J.; Skinner, Laura; Wong, Kitty Hf; Dixon, Lauren; Sutak, Judit; Harper, Steven J.; Pontrelli, Paola; Gesualdo, Loreto; Heerspink, Hiddo Lambers; Toto, Robert D.; Welsh, Gavin I.; Foster, Rebecca R.; Satchell, Simon C.; Butler, Matthew

doi:10.1172/jci.insight.154164

Cited by 18 publications

(13 citation statements)

References 106 publications

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“…The present study showed that MRAs significantly reduced UACR compared with placebo with background of ACEI/ARB, which may be related to the hemodynamic effects, the preservation of the glycocalyx and modulation of matrix metalloproteinase (MMP) activity by MRAs, and the protective effects for podocyte via the inhibition of Rac1 activity of MRAs [78, 79]. Nonsteroidal MRAs, with a high selectivity for MR, were superior to steroidal MRAs in the reduction of UACR.…”

Section: Discussionmentioning

confidence: 90%

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis

Yuan,

Gao,

Lin

et al. 2023

Am J Nephrol

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Introduction: The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in chronic kidney disease (CKD) are inconsistent. We aimed to summarize the significance of MRAs in treating CKD. Methods: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non–dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. Results: 53 trials with 6 different MRAs involving 22792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (WMD, -90.90 mg/g, 95% CI, -140.17 to -41.64 mg/g), 24-hour urinary protein excretion (WMD, -0.20 g, 95%CI, -0.28 to -0.12 g), eGFR (WMD, -1.99 ml/min/1.73 m2, 95% CI, -3.28 to -0.70 ml/min/1.73 m2), chronic renal failure events (RR, 0.86, 95% CI, 0.79 to 0.93) and cardiovascular events (RR, 0.84, 95% CI, 0.77 to 0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73 to 2.40) and hypotension (RR, 1.80, 95% CI, 1.41 to 2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56 to 0.75), but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79 to 1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57 to 0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02 to 1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26 to 25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22 to 1.22) increased the risk of breast disorders. Conclusions: In the CKD patients, MRAs, particularly in combination with ACEI/ARB, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increased the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs was superior in the reduction of more albuminuria with fewer peripheral edema events, and without the augment of breast disorders events.

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Section: Discussionmentioning

confidence: 90%

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis

Yuan,

Gao,

Lin

et al. 2023

Am J Nephrol

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“…It is known that diabetes causes damage to the EGlx [5, 20, 28–30, 38] and we have recently shown coronary microvascular EGlx damage, for the first time, in mice with DCM [30]. In our recent study we have shown that preservation of the coronary microvascular EGlx with angiopoietin 1 reduced perivascular oedema and improved diastolic function in both type 1 and 2 models of DCM [30].…”

Section: Introductionmentioning

confidence: 84%

“…Analysis of EGlx depth was performed using a macro in Image J which measures the anatomical distance between the fluorescence intensity peaks of lectin and R18 as an indication of EGlx depth as described previously [5]. Capillary (3-10 μm in diameter) cross-sections were selected for analysis by circularity (ratio of shortest and longest diameter, 0.8 to 1).…”

Section: Methodsmentioning

confidence: 99%

“…The distance between the peak signals from the lectin-488 and the R18 labels (peak-to-peak) was used as an indication of EGlx thickness. This method was automated using an Image J (NIH) macro to take multiple measurements in a preselected capillary loop as described previously [5]. Gaussian curves were applied to the raw intensity data of each plot for peak-to-peak measurements.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of MMP 2&9 protects the endothelial glycocalyx and improves diastolic function in diabetic cardiomyopathy

Buffonge,

Qiu,

Fawaz

et al. 2023

Preprint

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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-α 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-α 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-α 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 DeclarationsCompeting interestsThe authors have no competing interests to declare that are relevant to the content of this article.

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“…Extracellularly, glycocalyx alterations in CKD are partially dependent on the activation of mineralocorticoid receptors and its downstream target epithelial sodium channel on the surface of endothelial cells. In diabetic nephropathy, glycocalyx degradation is associated with mineralocorticoid receptor activation [21] and cholesterol deposition in glomerular endothelial cells [22], which may lead to increased glomerular albumin permeability. When exposing endothelial cells to glycocalyx precursors, such as fucoidan and hyaluronan, the glycocalyx is not degraded by from serum of patients with CKD.…”

Section: Kidney Diseasementioning

confidence: 99%

Therapeutic strategies targeting the endothelial glycocalyx

Machin

Sabouri

Zheng

et al. 2023

Current Opinion in Clinical Nutrition &Amp; Metabolic Care

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Purpose of review This review will highlight recent studies that have examined the endothelial glycocalyx in a variety of health conditions, as well as potential glycocalyx-targeted therapies. Recent findings A degraded glycocalyx is present in individuals that consume high sodium diet or have kidney disease, diabetes, preeclampsia, coronavirus disease 2019 (COVID-19), or sepsis. Specifically, these conditions are accompanied by elevated glycocalyx components in the blood, such as syndecan-1, syndecans-4, heparin sulfate, and enhanced heparinase activity. Impaired glycocalyx barrier function is accompanied by decreased nitric oxide bioavailability, increased leukocyte adhesion to endothelial cells, and vascular permeability. Glycocalyx degradation appears to play a key role in the progression of cardiovascular complications. However, studies that have used glycocalyx-targeted therapies to treat these conditions are scarce. Various therapeutics can restore the glycocalyx in kidney disease, diabetes, COVID-19, and sepsis. Exposing endothelial cells to glycocalyx components, such as heparin sulfate and hyaluronan protects the glycocalyx. Summary We conclude that the glycocalyx is degraded in a variety of health conditions, although it remains to be determined whether glycocalyx degradation plays a causal role in disease progression and severity, and whether glycocalyx-targeted therapies improve patient health outcomes. Future studies are warranted to investigate therapeutic strategies that target the endothelial glycocalyx.

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Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx

Cited by 18 publications

References 106 publications

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis

Effects of Mineralocorticoid Receptor Antagonists for Chronic Kidney Disease: A Systemic Review and Meta-Analysis

Inhibition of MMP 2&9 protects the endothelial glycocalyx and improves diastolic function in diabetic cardiomyopathy

Therapeutic strategies targeting the endothelial glycocalyx

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