Dataset Information

Effects of Chronic Kidney Disease on Nanomechanics of the Endothelial Glycocalyx Are Mediated by the Mineralocorticoid Receptor.

ABSTRACT: Endothelial mechanics control vascular reactivity and are regulated by the mineralocorticoid receptor (MR) and its downstream target, the epithelial Na⁺ channel (ENaC). Endothelial dysfunction is a hallmark of chronic kidney disease (CKD), but its mechanisms are poorly understood. We hypothesized that CKD disrupts endothelial mechanics in an MR/ENaC-dependent process.

Methods

Primary human endothelial cells were cultured with uremic serum derived from children with stage 3-5 (predialysis) CKD or adult hemodialysis (HD) patients or healthy controls. The height and stiffness of the endothelial glycocalyx (eGC) and cortex were monitored by atomic force microscopy (AFM) using an ultrasensitive mechanical nanosensor.

Results

In a stage-dependent manner, sera from children with CKD induced a significant increase in eGC and cortex stiffness and an incremental reduction of the eGC height. AFM measurements were significantly associated with individual pulse wave velocity and serum concentrations of gut-derived uremic toxins. Serum from HD patients increased MR expression and mechanical stiffness of the endothelial cortex, an effect reversed by MR and ENaC antagonists, decreased eNOS expression and NO bioavailability, and augmented monocyte adhesion.

Conclusion

These data indicate progressive structural damage of the endothelial surface with diminishing kidney function and identify the MR as a mediator of CKD-induced endothelial dysfunction.

SUBMITTER: Fels B

PROVIDER: S-EPMC9503126 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Effects of Chronic Kidney Disease on Nanomechanics of the Endothelial Glycocalyx Are Mediated by the Mineralocorticoid Receptor.

Fels Benedikt B Beyer Arne A Cazaña-Pérez Violeta V Giraldez Teresa T Navarro-González Juan F JF Alvarez de la Rosa Diego D Schaefer Franz F Bayazit Aysun K AK Obrycki Łukasz Ł Ranchin Bruno B Holle Johannes J Querfeld Uwe U Kusche-Vihrog Kristina K

International journal of molecular sciences 20220913 18

Endothelial mechanics control vascular reactivity and are regulated by the mineralocorticoid receptor (MR) and its downstream target, the epithelial Na<sup>+</sup> channel (ENaC). Endothelial dysfunction is a hallmark of chronic kidney disease (CKD), but its mechanisms are poorly understood. We hypothesized that CKD disrupts endothelial mechanics in an MR/ENaC-dependent process.<h4>Methods</h4>Primary human endothelial cells were cultured with uremic serum derived from children with stage 3-5 (p ...[more]

PMID: 36142571

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Project description:Rationale & objectiveTo comprehensively summarize the efficacy of mineralocorticoid receptor antagonists (MRAs) to improve kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease (CKD).Study designRelevant studies were identified from Medline and Scopus databases from their inception up to August 2023.Setting & study populationsPatients with nondialysis or dialysis CKD.Selection criteria for studiesSystematic reviews and meta-analyses (SR-MAs) of randomized controlled trials (RCTs) that investigated the efficacy of MRAs on kidney and CV outcomes in patients with nondialysis or dialysis CKD were included in this study.Data extractionCharacteristics of studies and participants, and treatment effects were extracted.Analytic approachEfficacy of MRAs was qualitatively summarized according to types of patients and MRAs.ResultsForty SR-MAs were included. When compared with placebo/usual care, steroidal MRAs (sMRAs) provided significant benefit in decreasing all-cause (pooled RRs of 0.38 [0.22-0.65] to 0.87 [0.77-0.98]) and CV mortality (pooled RRs of 0.34 [0.15-0.75] to 0.46 [0.28-0.76]) only in patients treated with dialysis, when compared with placebo. Nonsteroidal MRAs (nsMRAs) significantly lowered composite CV events in both nondialysis CKD (pooled RRs of 0.86 [0.79-0.94] to 0.92 [0.85-0.99]) and patients with diabetic kidney disease (DKD) (pooled RRs of 0.86 [0.78-0.95] to 0.88 [0.81-0.96]). In addition, nsMRAs showed significant benefit in reducing composite kidney outcomes in patients with either nondialysis CKD or DKD when compared with placebo. However, this efficacy was lower than sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with DKD. Moreover, both sMRAs and nsMRAs significantly increased the risk of hyperkalemia in patients with nondialysis CKD and DKD.LimitationsThe comparison between nsMRAs and SGLT2i is based on network meta-analyses. Consequently, additional head-to-head RCTs are necessary to confirm the advantages of SGLT2i over nsMRAs.ConclusionssMRAs offer benefits in reducing all-cause and cardiovascular mortality and composite CV events in patients treated with dialysis. nsMRAs improve kidney outcomes in patients with nondialysis CKD and DKD but increase hyperkalemia risk.

Dataset Information

Effects of Chronic Kidney Disease on Nanomechanics of the Endothelial Glycocalyx Are Mediated by the Mineralocorticoid Receptor.

Methods

Results

Conclusion

Publications

Effects of Chronic Kidney Disease on Nanomechanics of the Endothelial Glycocalyx Are Mediated by the Mineralocorticoid Receptor.

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