Sacubitril/valsartan treatment has differential effects in modulating diabetic kidney disease in db/db mice and KKAy mice compared with valsartan treatment

• Published in: American journal of physiology. Renal physiology Vol. 320; no. 6; pp. F1133 - F1151
• Main Authors: Myakala, Komuraiah, Jones, Bryce A., Wang, Xiaoxin X., Levi, Moshe
• Format: Journal Article
• Language: English
• Published: Bethesda American Physiological Society 01.06.2021
• Subjects: AMP; Angiotensin; Angiotensin II; Animal models; Congestive heart failure; Cyclic GMP; Deoxyribonucleic acid; Diabetes; Diabetes mellitus (non-insulin dependent); DNA; Inflammation; Interferon; Kidney diseases; Neprilysin; Peptides; Proteinuria; Renin; Rodents; Therapeutic targets; Vasoactive agents
• ISSN: 1931-857X; 1522-1466; 1522-1466
• DOI: 10.1152/ajprenal.00614.2020

The first-in-class drug sacubitril/valsartan, a combination of the angiotensin II receptor blocker valsartan and neprilysin inhibitor sacubitril, was tested for its effects in diabetic kidney disease using db/db mice and KKAy mice. We found that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease. We further revealed a new mechanism to cause inflammation, self-DNA-activated cGAS-STING signaling, which was activated in diabetic kidneys and prevented by sacubitril/valsartan or valsartan treatment. Although renin-angiotensin blockade has shown beneficial outcomes in patients with diabetes, renal injury progresses in most of these patients. Therefore, there remains a need for new therapeutic targets in diabetic kidney disease. Enhancement of vasoactive peptides, such as natriuretic peptides, via neprilysin inhibition, has been a new approach. A first-in-class drug, sacubitril/valsartan (Sac/Val), a combination of the angiotensin II receptor blocker Val and neprilysin inhibitor prodrug Sac, has been shown to be more effective than renin-angiotensin blockade alone in the treatment of heart failure with reduced ejection fraction. In this study, we tested the effects of Sac/Val in diabetic kidney disease. We administered Sac/Val or Val to two type 2 diabetes mouse models, db/db mice or KKAy mice. After 3 mo of treatment, Sac/Val attenuated the progression of proteinuria, glomerulosclerosis, and podocyte loss in both models of diabetic mice. Val shared a similar improvement but to a lesser degree in some parameters compared with Sac/Val. Sac/Val but not Val decreased the blood glucose level in KKAy mice. Sac/Val exerted renal protection through coordinated effects on antioxidative stress and anti-inflammation. In both diabetic models, we revealed a new mechanism to cause inflammation, self-DNA-activated cGMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, which was activated in diabetic kidneys and prevented by Sac/Val or Val treatment. The present data suggest that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease, and its effectiveness could be better than Val alone. NEW & NOTEWORTHY The first-in-class drug sacubitril/valsartan, a combination of the angiotensin II receptor blocker valsartan and neprilysin inhibitor sacubitril, was tested for its effects in diabetic kidney disease using db/db mice and KKAy mice. We found that Sac/Val has sufficient therapeutical potential to counter the pathophysiological effects of diabetic kidney disease. We further revealed a new mechanism to cause inflammation, self-DNA-activated cGAS-STING signaling, which was activated in diabetic kidneys and prevented by sacubitril/valsartan or valsartan treatment.