Although renin-angiotensin blockade has shown the 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 angiotensin II receptor blocker valsartan and neprilysin inhibitor prodrug sacubitril, has been shown 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 the diabetic kidney disease. We administered Sac/Val or valsartan to two type 2 diabetes mouse models, db/db mice or KKAy mice. After 3-month treatment, Sac/Val attenuated the progression of proteinuria, glomerulosclerosis, and podocyte loss in both models of diabetic mice. Valsartan shared the similar improvement but to a lesser degree in some parameters compared to Sac/Val. Sac/Val but not valsartan decreased the blood glucose level in KKAy mice. Sac/Val exerted renal protection through coordinated effects on anti-oxidative stress and anti-inflammation. In both diabetic models, we revealed a new mechanism to cause inflammation, self DNA activated cGAS-STING signaling, which was activated in diabetic kidneys and prevented by Sac/Val or valsartan treatment. 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 valsartan alone.
Potential effects and application prospect of angiotensin receptor-neprilysin inhibitor in diabetic kidney disease
