ACE Inhibition and GLP1 Receptor Agonism Have Direct Effects on the Glomerular Capillary Wall to Reduce Glomerular Albumin Permeability in Diabetes

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Background: The mainstay of therapeutics to protect from diabetic kidney disease are anti-hypertensive and anti-glycaemic agents, yet they seem to have additional protective effects on albuminuria. Our validated glomerular permeability assay was developed to directly measure the albumin permeability (Ps'alb) of capillary loops within individually trapped glomeruli. This ex vivo assay is independent of haemodynamic factors and tubular albumin handling - factors known to affect urine protein concentrations. Using our glomerular Ps'alb assay, we aimed to understand whether renoprotective standard of care and new compounds could target the cells of the glomerular filtration barrier (GFB) directly. Methods: A rat model of type 1 diabetes was utilised, whereby male Wistar rats were injected with streptozotocin (STZ, 50mg/kg I.P.). Rat glomeruli were isolated from perfused kidneys at week 4 and received a 1-hour treatment in 10% plasma with semaglutide (a glucagon-like peptide-1 receptor agonist), enalapril (an angiotensin-converting enzyme inhibitor), empagliflozin (a sodium-glucose co-transporter 2 inhibitor), angiopoietin-1 (a positive control) or vehicle. Our glomerular Ps'alb assay was used to measure changes in albumin permeability. Results: Rats given STZ were significantly hyperglycaemic at week 1, which was sustained, confirming diabetes (P<0.001). Diabetic rats developed albuminuria, with a significant increase in urine albumin:creatinine ratio at week 4 (P=0.0014). Diabetes also induced a significant increase in Ps'alb (P=0.005), which was ameliorated by both semaglutide and enalapril to a level comparable with nondiabetic glomeruli. Empagliflozin had no significant effect on the diabetes-induced increase in Ps'alb. In control glomeruli, semaglutide and enalapril alone had no effect compared with vehicle, suggesting no effect on otherwise healthy capillaries. Conclusions: Semaglutide and enalapril 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. Funding: Commercial Support - Novo Nordisk

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