Abstract
Abstract Background and Aims Obesity, hyperglycemia and hypertension are critical risk factors for development of diabetic kidney disease (DKD). Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular and renal outcomes in type 2 diabetes patients. Here, we characterized the effect of long-acting GLP-1R agonist semaglutide alone and in combination with an ACE inhibitor in a model of hypertension-accelerated, advanced DKD facilitated by adeno-associated virus-mediated renin overexpression (ReninAAV) in uninephrectomized (UNx) female db/db mice. Method 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 tail-cuff blood pressure evaluation at week 1 and 10, plasma/urine biochemistry, kidney histopathology as well as RNA sequencing. Results Semaglutide robustly reduced hyperglycemia, hypertension and albuminuria concurrent with notable improvements in glomerulosclerosis severity, urine/renal kidney injury molecule-1 (KIM-1) levels. Furthermore, semaglutide suppressed gene expression markers of extracellular matrix modelling and immune system activation. Co-administration of lisinopril further ameliorated hypertension, glomerulosclerosis as well as markers of fibrogenesis and inflammation. Conclusion Semaglutide improves disease hallmarks in the db/db UNx-ReninAAV mouse model of advanced DKD. Renal outcomes were further improved by combined antihypertensive standard-of-care. These data display the translatability of the db/db UNx-ReninAAV mouse model of DKD.
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