Renal Transcriptomic Profiling Reveals Beneficial Effects of Semaglutide and Lisinopril in Advanced Diabetic Kidney Disease

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 antihypertensive standard-of-care (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, female 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, albuminuria and glomerulosclerosis severity. Co-administration of lisinopril further ameliorated hypertension and glomerulosclerosis. Renal gene expression changes after semaglutide mono- and combination treatment were primarily associated with the immune system and extracellular matrix organization. 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 suppresses gene expression markers of ECM remodeling and immune system activation. Outcomes were further improved by combined antihypertensive standard-of-care.