Abstract: TH-PO0372
Mineralocorticoid Receptor Antagonism and Glucagon-Like Peptide 1 Receptor Agonism Have Direct Effects on Glomerular Cells to Reduce Glomerular Albumin Permeability in Diabetes
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Crompton, Michael, University of Bristol, Bristol, United Kingdom
- Stowell-Connolly, Holly, University of Bristol, Bristol, United Kingdom
- Mills, Jack, University of Bristol, Bristol, United Kingdom
- Frost, Patrick Wa, University of Bristol, Bristol, United Kingdom
- Butler, Matthew J., University of Bristol, Bristol, United Kingdom
- Welsh, Gavin Iain, University of Bristol, Bristol, United Kingdom
- Lindsay, Ross, Novo Nordisk A/S Global Research, Måløv, Denmark
- Nagao, Ryan J., Novo Nordisk A/S Global Research, Måløv, Denmark
- Benardeau, Agnes M., Novo Nordisk A/S Global Research, Måløv, Denmark
- Østergaard, Mette Viberg, Novo Nordisk A/S Global Research, Måløv, Denmark
- Foster, Rebecca R., University of Bristol, Bristol, United Kingdom
- Satchell, Simon C., University of Bristol, Bristol, United Kingdom
Background
Diabetes mellitus is a major global health challenge, and diabetic kidney disease (DKD) remains its most serious complication in terms of morbidity, mortality and healthcare costs. The mainstay of therapeutics to protect from DKD are anti-hypertensive and anti-glycaemic agents, yet they seem to have additional protective effects on albuminuria. Damage to the glomerular filtration barrier (GFB) causes protein leakage or loss of filtration capacity, both of which drive progression to kidney failure. Our validated glomerular permeability assay was developed to directly measure the albumin permeability (Ps’alb) of capillary loops within individually trapped glomeruli, independent of haemodynamic factors and tubular albumin handling. Using our glomerular Ps’alb assay, we aimed to understand whether established and emerging renoprotective compounds could exert direct effects on GFB in diabetes.
Methods
Male Han Wistar rats were injected with streptozotocin (STZ, 50mg/kg I.P.) to induce type 1 diabetes and were perfused 4 weeks post-STZ. Isolated glomeruli were incubated with 10% rat plasma for 1 hour at 37°C, and treated with clinically relevant doses of atrasentan, empagliflozin, finerenone, lisinopril, semaglutide, angiopoietin-1 (positive control) or vehicle. Our glomerular Ps’alb assay was used to measure changes in albumin permeability.
Results
Diabetes induced albuminuria was observed at week 4 post-STZ, with significant increases in urine albumin:creatinine ratio and Ps’alb (both P<0.0001). Finerenone- and semaglutide-treated diabetic glomeruli had a significant reduction in Ps’alb (finerenone 3000 nM, P<0.0001; semaglutide 3 nM, P=0.015), to a level comparable with control glomeruli. In addition, finerenone and semaglutide exhibited a dose-dependent response on Ps’alb. Atrasentan, empagliflozin and lisinopril, at the concentrations used, had no significant effect on the diabetes-induced increase in Ps’alb.
Conclusion
MR antagonism and GLP1 receptor agonism, by finerenone and semaglutide, both ameliorate the diabetes-induced increase in Ps’alb, demonstrating a direct effect on the cells of the GFB in diabetes. Thus, a greater understanding of the mechanisms of glomerular protection mediated by these renoprotective compounds is needed to identify novel therapeutic strategies.
Acknowledgment
This work was funded by Novo Nordisk.
Funding
- Commercial Support – Novo Nordisk