Abstract: SA-PO222
Nephroprotective Effects of Semaglutide in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic - II
November 05, 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
- Bak, Stine Thorhauge, Gubra, Hoersholm, Denmark
- Dalbøge, Louise, Gubra, Hoersholm, Denmark
- Christensen, Michael, Gubra, Hoersholm, Denmark
- Secher, Thomas, Gubra, Hoersholm, Denmark
- Endlich, Nicole, NIPOKA GmbH, Greifswald, Germany
- Drenic, Vedran, NIPOKA GmbH, Greifswald, Germany
- Madsen, Martin Roenn, 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). 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.
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, plasma/urine biochemistry, kidney histopathology and RNA sequencing.
Results
Semaglutide robustly reduced hyperglycemia, hypertension and albuminuria concurrent with notable improvements in glomerulosclerosis severity, podocyte filtration slit density, urine/renal kidney injury molecule-1 (KIM-1) levels and gene expression markers of inflammation and fibrogenesis. Co-administration of lisinopril further ameliorated hypertension and glomerulosclerosis.
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.