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Abstract: SA-PO444

Renal Cell Type-Associated Therapeutic Effects of Semaglutide in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Bak, Stine Thorhauge, Gubra, Hoersholm, Denmark
  • Dalbøge, Louise, Gubra, Hoersholm, Denmark
  • Christensen, Michael, Gubra, Hoersholm, Denmark
  • Secher, Thomas, Gubra, Hoersholm, Denmark
  • Hansen, Henrik H., Gubra, Hoersholm, Denmark
  • Rune, Ida, Gubra, Hoersholm, Denmark
  • Fink, Lisbeth N., Gubra, Hoersholm, Denmark
  • Østergaard, Mette Viberg, Gubra, Hoersholm, Denmark
Background

Obesity, hyperglycemia and hypertension are critical risk factors for development of diabetic kidney disease (DKD). While emerging evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients, their mode of action is presently unclear. Using paired bulk and single-nucleus RNA sequencing (RNAseq), we profiled renal transcriptome signatures of the long-acting GLP-1R agonist semaglutide alone and in combination with the ACE inhibitor lisinopril in a model of hypertension-accelerated, advanced DKD facilitated by adeno-associated virus-mediated renin overexpression (ReninAAV) in uninephrectomized (UNx) female db/db mice.

Methods

Seven weeks after ReninAAV administration and six weeks post-UNx, db/db UNx-ReninAAV mice were administered (q.d.) vehicle, semaglutide (30 nmol/kg, s.c.) or semaglutide (30 nmol/kg, s.c.) + lisinopril (30 mg/kg, p.o.) for 11 weeks. Endpoints included blood pressure, urine biochemistry, kidney histopathology as well as paired bulk and single-nucleus RNA seq. Cell type deconvolution was performed by referencing expression of treatment-affected genes across all major kidney cell types using single nuclei RNAseq.

Results

Semaglutide robustly reduced hyperglycemia, hypertension and albuminuria concurrent with reduction in glomerulosclerosis severity. Co-administration of lisinopril further ameliorated hypertension and glomerulosclerosis. Gene expression affected by both semaglutide mono- and combination treatment were primarily associated with the immune system and extracellular matrix remodeling. Semaglutide promoted discrete renal gene expression changes in db/db UNx-ReninAAV mice with notable suppression of macrophage-associated genes. Combined semaglutide and lisinopril administration resulted in more widespread transcriptome changes in several renal cell types, including macrophages, mesangial cells, podocytes and proximal tubule cells.

Conclusion

Semaglutide improves disease hallmarks in the db/db UNx-ReninAAV mouse model of advanced DKD and improves renal transcriptome signatures. Outcomes were further improved by combined antihypertensive standard-of-care.

Funding

  • Commercial Support – Gubra