@article{aac146063b4c4653ad35551c214382fb,
title = "Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx",
abstract = "The glomerular endothelial glycocalyx (GEnGlx) forms the first part of the glomerular filtration barrier. Previously, we showed that mineralocorticoid receptor (MR) activation caused GEnGlx damage and albuminuria. In this study, we investigated whether MR antagonism could limit albuminuria in diabetes and studied the site of action. Streptozotocin-induced diabetic Wistar rats developed albuminuria, increased glomerular albumin permeability (Ps{\textquoteright}alb), and increased glomerular matrix metalloproteinase (MMP) activity with corresponding GEnGlx loss. MR antagonism prevented albuminuria progression, restored Ps{\textquoteright}alb, preserved GEnGlx, and reduced MMP activity. Enzymatic degradation of the GEnGlx negated the benefits of MR antagonism, confirming their dependence on GEnGlx integrity. Exposing human glomerular endothelial cells (GEnC) to diabetic conditions in vitro increased MMPs and caused glycocalyx damage. Amelioration of these effects confirmed a direct effect of MR antagonism on GEnC. To confirm relevance to human disease, we used a potentially novel confocal imaging method to show loss of GEnGlx in renal biopsy specimens from patients with diabetic nephropathy (DN). In addition, patients with DN randomized to receive an MR antagonist had reduced urinary MMP2 activity and albuminuria compared with placebo and baseline levels. Taken together, our work suggests that MR antagonists reduce MMP activity and thereby preserve GEnGlx, resulting in reduced glomerular permeability and albuminuria in diabetes.",
author = "Michael Crompton and Ferguson, {Joanne K.} and Ramnath, {Raina D.} and Onions, {Karen L.} and Ogier, {Anna S.} and Monica Gamez and Down, {Colin J.} and Laura Skinner and Wong, {Kitty H.} and Dixon, {Lauren K.} and Judit Sutak and Harper, {Steven J.} and Paola Pontrelli and Loreto Gesualdo and Heerspink, {Hiddo L.} and Toto, {Robert D.} and Welsh, {Gavin I.} and Foster, {Rebecca R.} and Satchell, {Simon C.} and Butler, {Matthew J.}",
note = "Funding Information: The authors would like to thank the Medical Research Council in addition to the Wolfson Foundation for establishing the Wolfson Bioimaging Facility and gratefully acknowledge the Wolfson Bioimaging Facility for their support and assistance in this work. Specifically, we thank Stephen Cross for helping to develop our automated peak-to-peak methodology. Kidney Research UK grants (RP_031_20180306, JF-S/RP/2015/10, RP_002_20190917, ID_004_20170330, and IN_004_20190305); a Diabetes UK grant (18/0005795); a British Heart Foundation grant (PG/15/81/31740); and a Medical Research Council Clinical Research Training Fellowship grant (MR/M018237/1 for MJB) also funded this work. PP, LG, HLH, and SCS are members of the Biomarker Enterprise to Attack Diabetic Kidney Disease (BEAt-DKD) consortium; this project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115974. The joint undertaking (JU) receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation programme and European federation of Pharmaceutical Industries and Associations (EFPIA) and Juvenile Diabetes Research Foundation (JDRF). Any dissemination of results reflects only the author{\textquoteright}s view; the JU is not responsible for any use that may be made of the information it contains. Publisher Copyright: {\textcopyright} 2023, Crompton et al.",
year = "2023",
month = mar,
day = "8",
doi = "10.1172/jci.insight.154164",
language = "English",
volume = "8",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "AMER SOC CLINICAL INVESTIGATION INC",
number = "5",
}