Platelets are relevant mediators of renal injury induced by primary endothelial lesions

Abstract

Schwarzenberger C, Sradnick J, Lerea KM, Goligorsky MS, Nieswandt B, Hugo CP, Hohenstein B. Platelets are relevant mediators of renal injury induced by primary endothelial lesions. studies have suggested a prominent (pro)inflammatory and harmful role of platelets in renal disease, and newer work has also demonstrated platelet release of proangiogenic factors. In the present study, we investigated the role of platelets in a mouse model of selective endothelial cell injury using either platelet depletion or the pharmacological P2Y12 receptor blocker clopidogrel as an interventional strategy. The concanavalin A/anti-concanavalin A model was induced in left kidneys of C57bl/6J wild-type mice after initial platelet depletion or plateletinhibiting therapy using clopidogrel. FACS analysis of glycoprotein IIb/IIIa/P-selectin double-positive platelets and platelet-derived microparticles demonstrated relevant platelet activation after the induction of selective endothelial injury in mice. Enhanced platelet activation persisted for 5 days after disease induction and was accompanied by increased amounts of circulating platelet-derived microparticles as potential mediators of a prolonged procoagulant state. By immunohistochemistry, we detected significantly reduced glomerular injury in platelet-depleted mice compared with control mice. In parallel, we also saw reduced endothelial loss and a consequently reduced repair response as indicated by diminished proliferative activity. The P2Y12 receptor blocker clopidogrel demonstrated efficacy in limiting platelet activation and subsequent endothelial injury in this mouse model of renal microvascular injury. In conclusion, platelets are relevant mediators of renal injury induced by primary endothelial lesions early on, as demonstrated by platelet depletion as well as platelet inhibition via the P2Y12 receptor. While strategies to prevent platelet-endothelial interactions have shown protective effects, the contribution of platelets during renal regeneration remains unknown. renal microvascular endothelial injury; platelets; thrombotic microangiopathy; clopidogrel; platelet microparticles THE RENAL MICROVASCULATURE represents a primary or secondary target in various types of glomerulonephritis. During the progression of kidney disease, loss of microvascular capillaries is accompanied by progressive renal scarring (7-9, 22, 41). To complement a variety of humoral factors, inflammatory cells frequently contribute to renal pathophysiology, finally leading to functional deterioration and the loss of intrinsic renal cells.

Impact of KDIGO-Defined Acute Kidney Injury on Mortality after Percutaneous Coronary Intervention for Acute Myocardial Infarction

“…P2Y12 receptor antagonists were also an independent predictor of AKI. Some experimental animal data show that P2Y12 inhibition prevents glomerular injury and protects both glomerular and peritubular capillaries, but data on P2Y12 inhibition and AKI in patients are lacking [23]. Moreover, patients who did not receive P2Y12 receptor antagonists were sicker (older, with more STEMI, a higher prevalence of cardiogenic shock, diabetes, renal dysfunction and anemia, more IABP were implanted, they bled more, received more IIb/IIIa receptor antagonists, they had less radial access, lower TIMI flow after PCI, and higher contrast/eGFR ratios).…”

Combination of Mean Platelet Volume/Platelet Count Ratio and the APACHE II Score Better Predicts the Short-Term Outcome in Patients with Acute Kidney Injury Receiving Continuous Renal Replacement Therapy

“…Several studies have suggested platelet activation exacerbates renal injury [10-11]. Our previous study [35] also showed that in rat renal ischemia-reperfusion injury, P-selectin was widely expressed in renal tissue, especially in renal tubular epithelial cells.…”

“…Platelets play an important role in the processes of coagulation and inflammatory, and it has been shown that platelet activation exacerbates renal injury [10]. Recently, Jansen and colleagues found during renal ischemia reperfusion injury, necrotic cell-derived DNA led to platelet activation, platelet-granulocyte interaction, and subsequent neutrophil extracellular trap formation, leading to renal inflammation and further increase in tissue injury [11].…”

Extracellular vesicles and microvascular pathology: Decoding the active dialogue

“…High numbers of circulating platelet‐derived MVs were likely mediators of a prolonged procoagulant state. In platelet‐depleted mice, glomerular injury and platelet activation were significantly reduced compared with control mice . Lung pathology could also be triggered by platelet‐derived MVs, as shown in vitro in a two‐insult model of PMN‐induced human pulmonary microvascular endothelial cell damage.…”