Kidney Week

Abstract: TH-PO193

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

Session Information

• Diabetic Kidney Disease: Basic - I
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Crompton, Michael, University of Bristol, Bristol, Bristol, United Kingdom

Michael Crompton,

• Butler, Matthew J., University of Bristol, Bristol, Bristol, United Kingdom

Matthew J. Butler,

• Welsh, Gavin Iain, University of Bristol, Bristol, Bristol, United Kingdom

Gavin Iain Welsh,

• Bhayana, Sagar, Novo Nordisk AS, Bagsvaerd, Hovedstaden, Denmark

Sagar Bhayana,

• Foster, Rebecca R., University of Bristol, Bristol, Bristol, United Kingdom

Rebecca R. Foster,

• Benardeau, Agnes M., Novo Nordisk AS, Bagsvaerd, Hovedstaden, Denmark

Agnes M. Benardeau,

• Satchell, Simon C., University of Bristol, Bristol, Bristol, United Kingdom

Simon C. Satchell,

Group or Team Name

• Bristol Renal

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.

Conclusion

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 –