Introduction & Objective: Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients, however, their mode of action at the kidney level 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 an ACE inhibitor in a state-of-the-art mouse model of hypertension-accelerated advanced DKD.
Methods: Female db/db mice received a single i.v. injection of renin-encoding adeno-associated virus (ReninAAV) followed by uninephrectomy (UNx) one week later. 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 histology and paired bulk and single-nucleus RNAseq.
Results: Semaglutide improved hyperglycemia, hypertension and albuminuria concurrent with reduction in glomerulosclerosis severity in db/db ReninAAV-UNx mice. Co-administration of lisinopril further reduced hypertension and glomerulosclerosis. Renal transcriptome changes induced by semaglutide mono- and combination treatment were primarily linked to the immune system and extracellular matrix remodeling. 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 ReninAAV-UNx mouse model of advanced DKD associated with modulation of several renal cell types. Therapeutic outcomes and renal transcriptome signatures were further improved by combined antihypertensive standard-of-care.
M. Tozzi: None. H.H. Hansen: Employee; Gubra. M. Christensen: Employee; Gubra.
