Abstract: TH-PO0393
Soluble Guanylate Cyclase Activator plus SGLT2 Inhibition Preserves Podocytes and Reduces Inflammation in Experimental Diabetic Nephropathy
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Ma, Hualin, Shenzhen People's Hospital, Shenzhen, Guangdong, China
- Zhong, Jianyong, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Pieper, Michael P., Boehringer Ingelheim International GmbH, Ingelheim am Rhein, RP, Germany
- Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Fogo, Agnes B., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
In diabetic nephropathy (DN), oxidative stress and endothelial dysfunction can impair nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling, which is important for kidney homeostasis. Although sodium–glucose cotransporter 2 inhibitors (SGLT2i) are standard of carein DN, substantial residual renal risk persists. sGC activators reduce proteinuria in clinical trials, but it is unknown whether sGC activation provides additional kidney protection beyond SGLT2i. We tested the effects of an sGC activator combined with empagliflozin in an endothelial nitric oxide synthase (eNOS) knockout mouse model of DN.
Methods
eNOS-/- db/db mice (C57BL/6 strain) were assigned to five groups (n=10-22/group): 1) Baseline (age 10 wks); 2) Control (vehicle, age wk 10-18); or treatment wk 10-18 with 3) sGC activator; 4) Empagliflozin; 5) Combination (sGC activator + empagliflozin).
Results
Urinary cGMP levels were lower in vehicle-treated mice at week 18 vs baseline and were restored by the sGC activator and the combination. Empagliflozin lowered blood glucose, with a further reduction in the combination group. Only the combination significantly reduced blood pressure. Empagliflozin and the combination improved GFR toward baseline, whereas the sGC activator reduced albuminuria vs control. The combination preserved podocyte density, whereas empagliflozin alone did not. Glomerular injury scores increased in controls at week 18 vs baseline and were significantly reduced by all treatments. Empagliflozin and the sGC activator reduced glomerular collagen IV deposition vs control; the combination showed a numerical decrease. In the tubulointerstitium, only the combination significantly reduced collagen I staining. F4/80+ macrophage infiltration increased in controls at week 18 and was significantly reduced only by the combination.
Conclusion
In experimental DN, adding an sGC activator to SGLT2 inhibition provides complementary kidney protection, including improved podocyte preservation and reduced renal inflammation, with limited incremental effects on select fibrosis markers.
Funding
- Commercial Support – Boehringer Ingelheim Pharma GmbH & Co. KG