479-P: Inhibition of the NLRP3 Inflammasome by MCC950 Accelerates Renal Injury in Diabetes Model

Abstract

Background: Previous studies suggest that NLRP3 inflammasome activation could have pathological relevance in diabetic kidney disease (DKD). A recent study demonstrated that NLRP3 inhibition in a preventional approach in db/db mice provided reno-protection, potentially via a ROS dependent mechanism. We aimed to examine the therapeutical potential of the NLRP3 inflammasome inhibitor, MCC950 in a more clinically relevant interventional approach in a model of DKD and its impact on renal pathology. Methods: Diabetes was induced by streptozotocin in ApoE-/- mice. A subgroup of control and diabetic mice was treated with MCC950 (5mg/kg/3 times/week). Treatment was commenced after 5 or 9 weeks of diabetes and continued for another 5 or 9 weeks for the assessment of renal gene expression as well its impact on albuminuria and renal morphology, respectively. Results: Diabetes-induced mesangial expansion was further increased in MCC950 treated diabetic mice when compared to untreated diabetic group (18.9±0.6% vs. 16.3±0.7%, respectively). MCC950 treated diabetic mice showed a trend of increased albuminuria when compared to untreated diabetic mice (43±9 vs. 31±5 ug/24hrs, respectively). Gene expression of markers of fibrosis (fibronectin, collagen IV, α-smooth muscle actin and PCNA) and pro-oxidant enzymes (Nox2 and Nox4) were upregulated in diabetic mice compared to nondiabetic controls. These changes were further upregulated in MCC950-treated diabetic mice when compared to untreated diabetic mice. In addition, mRNA expression of pro-inflammatory markers (MCP-1 and IL-6) were increased in untreated diabetic animals as compared to controls and MCC950 treatment did not show additional upregulation of these parameters. Conclusions: The present study indicates that inhibition of the NLRP3 inflammasome by MCC950 after establishment of disease, may not have a reno-protective effect. Our data rather shows an adverse effect of this drug at least in this model of DKD. Disclosure J.A. Østergaard: None. J.C. Jha: None. A. Sharma: None. A. Dai: None. M.E. Cooper: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mundipharma International. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novartis AG, Sanofi-Aventis, Servier. J.B. de Haan: Research Support; Self; Bayer Inc., Reata Pharmaceuticals. K. Jandeleit-Dahm: None.