Platelet inhibition by ticagrelor is protective against diabetic nephropathy in mice

Abstract

Diabetic nephropathy (DN) is a major complication of diabetes and is associated with high risk for cardiovascular mortality, which is partially related to elevated platelet activity. Platelets are also active players in inflammation and fibrosis. In this study, we examine the effect of ticagrelor‐induced platelet inhibition on the development of DN. DN was induced by unilateral nephrectomy followed by streptozotocin injections for 5 days. Mice received ticagrelor (300 mg/kg) or vehicle every other day, for 16 weeks. Experimental groups: non‐diabetic control, diabetic control, non‐diabetic ticagrelor, and diabetic ticagrelor. Ticagrelor treatment in diabetic mice lowered urinary albumin excretion, it prevented diabetes‐induced mesangial matrix expansion, podocyte effacement, and glomerular endothelial cell injury, which includes loss of endothelial fenestrations, ICAM‐1 expression, and PECAM expression. In addition, ticagrelor treatment prevented collagen IV deposition and macrophage infiltration in the tubulointerstitium and these diabetic mice showed lower systemic and tubular inflammation and tubular apoptosis. This tubular protection is likely to be a result of protection to the glomerular endothelium by ticagrelor, which reduces albuminuria and albumin toxicity to the tubules and reduced tubular and interstitial inflammation and fibrosis. In conclusion, ticagrelor‐induced platelet inhibition protects against renal injury in diabetic mice, likely by protecting the glomerular endothelial cells.

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis

“… 65 Subsequent mechanistic studies in a mouse model for diabetic nephropathy demonstrated that the platelet P2Y12 inhibitor ticagrelor could counteract disease progression by lowering albuminuria, mesangial matrix expansion, macrophage infiltration, and fibrosis. 66 Future studies with selective platelet inhibitors such as GLP-1 analogues 67 could well augment our therapeutic options in progressive ischemia-associated diseases of the kidney.…”

Dysregulated coagulation system links to inflammation in diabetic kidney disease

“…It is therefore essential to understand the changes of coagulation factors in DKD with respect to its critical roles involving the activation of the complement and the consequent inflammation-induced fibrosis in DKD. The correction of abnormality of the coagulation factors is beneficial for patients with DKD as it not only prevents thrombosis but also kidney failure (75,76). The following sections will provide a summary of the dysregulations of critical factors in the coagulation system in DKD and their involvement in inflammation, along with their relevance to the progression of DKD.…”

The Role of Platelets in Diabetic Kidney Disease

“…In addition to its platelet-inhibition effect, ticagrelor has been shown to be effective in the treatment of acute coronary syndromes (ACS) and kidney disease. The effect of ticagrelor in DKD was examined by Uil et al [ 179 ]. They studied the effect of platelet inhibition by ticagrelor in an STZ-induced T1DM mouse model.…”