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Adiponectin reduces glomerular endothelial glycocalyx disruption and restores glomerular barrier function in a mouse model of type 2 diabetes

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posted on 2024-03-26, 18:00 authored by Sarah Fawaz, Aldara Martin Alonso, Yan Qiu, Raina Ramnath, Holly Stowell-Connolly, Monica Gamez, Carl May, Colin Down, Richard J. Coward, Matthew J. Butler, Gavin I. Welsh, Simon C. Satchell, Rebecca R. Foster

Adiponectin has vascular anti-inflammatory and protective effects. Whilst adiponectin is known to protect against the development of albuminuria, historically the focus has been on podocyte protection within the glomerular filtration barrier (GFB). The first barrier to albumin in the GFB is the endothelial glycocalyx (eGlx), a surface gel-like barrier covering glomerular endothelial cells (GEnC). In diabetes, eGlx dysfunction occurs before podocyte damage, hence we hypothesized that adiponectin could protect from eGlx damage to prevent early vascular damage in diabetic kidney disease (DKD). Globular adiponectin (gAd) activated AMPK signalling in human GEnC through AdipoR1. It significantly reduced eGlx shedding and the TNFα-mediated increase in syndecan-4 (SDC4) and MMP2 mRNA expression in GEnC in vitro. It protected against increased TNFα mRNA expression in glomeruli isolated from db/db mice, and genes associated with glycocalyx shedding (SDC4, MMP2 and MMP9). In addition, gAd protected against increased glomerular albumin permeability (Ps’alb) in glomeruli isolated from db/db mice, when administered to mice (i.p) and when applied directly to glomeruli (ex vivo). Ps’alb was inversely correlated with eGlx depth in vivo. In summary, adiponectin restored eGlx depth, which was correlated with improved glomerular barrier function, in diabetes.

Funding

SF has received funding from Innovative Medicines Initiative 2 Joint Undertaking of Biomarker Enterprise to Attack Diabetic Kidney Disease (BEAt-DKD) consortium. AMA was funded by Kidney Research UK project grant RP_005_20221128 and Elizabeth Blackwell Institute MRC Confidence in Concepts award. YQ was funded by British Heart Foundation project grants PG/16/35/32139 and PG/20/7/34849). RR was funded by Diabetes UK project grant 18/0005795 and Kidney Research UK project grant KS_RP_002_20190917. HSC was funded by a Wellcome Trust Partnership Award Fellowship 2023. MG was funded by British Heart Foundation project grant PG/20/10187. CM was funded by Diabetes UK project grant 19/0006037. CD was funded by David Telling Charitable Trust. RJC 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 JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and JDRF. Any dissemination of results reflects only the author's view; the JU is not responsible for any use that may be made of the information it contains. MJB was funded by a Kidney research UK development grant.

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