#1593 ARGDRR, a novel disintegrin, attenuates AKI to CKD-related renal fibrosis

Abstract

Abstract Background and Aims Acute kidney injury (AKI) can lead to progress renal fibrosis, resulting in chronic kidney disease (CKD) and end stage renal disease (ESRD). Nevertheless, the underlying pathological mechanisms remain unclear. Platelet activation has been demonstrated as one of the important factors involved in the pathophysiology of AKI, and studies show the therapeutic potential for using platelet inhibitors or antagonists in ischemia-reperfusion (IR)-induced AKI models. However, drug-induced side effects, including thrombotic microangiopathies (TMA)-related kidney damage, thrombocytopenia and bleeding, hinder clinical application in AKI or CKD treatment. Our newly developed dual effect disintegrin, ARGDRR, is derived from snake venom exert a high affinity to αIIbβ3 and αvβ3 binding affinity without causing bleeding and other thrombosis-related side effects. Method We performed a unilateral ischemia-reperfusion injury (UIRI) model to investigate integrin αIIb(Itga2b) and β3(Itgb3) mRNA levels in the injured kidney for 15 days. For exploring the therapeutic efficiency of ARGDRR in AKI, we administered ARGDRR post-ischemic injury and measured platelet activation after 24 hours using quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC) for Itgb3, Lcn2, and CD42b. For exploring the therapeutic efficiency of ARGDRR in CKD progression, we administrated ARGDRR daily for 15 days after IRI with nephrectomy, and examined the difference of renal dysfunction, renal fibrosis, and cell death compared to sham group. Results We found that platelet activation with progressively increased mRNA level of platelet glycoprotein IIb-GPIIIa (Itga2b and Itgb3) in the UIRI kidney over time. After 24 hr of ischemic AKI, ARGDRR administration reduced Lcn2 and Itgb3 mRNA level and CD42b positive area in the kidney, indicating its efficacy in protecting the kidneys by inhibiting platelet activation and aggregation. In AKI to CKD transition, serum creatine and blood urea nitrogen (BUN) were significantly lower both in efficacious and high dose of ARGDRR administration group. ARGDRR significantly reduced CD42b expression and increased LTL positive area. Also, ARGDRR administration alleviated renal fibrosis, cell apoptosis and senescence-related molecules p21 and Ctgf expression in the AKI to CKD transition. Conclusion Our results have successfully proved our hypothesis that disintegrin-ARGDRR has the potential for renal protection in the transition of AKI to CKD through inhibition of platelet activation and aggregation during acute injury.