Abstract 143: Role of Chronic Kidney Disease Promoted Caspase-1 Activation in Neointimal Hyperplasia

Abstract

The major cause of vascular access failure is venous stenosis due to neointimal hyperplasia (NH) [62]. Vascular smooth muscle cells (VSMC) are critical for the development of NH lesions, as they have the ability to modulate their phenotype from “contractile” to a “synthetic” in the presence of uremia, through the regulation of sensor genes for uremia danger signals and VSMC-specific differentiation genes. Recent research indicates that Caspase-1 (casp-1) activation plays an essential role in sensing metabolic danger signal-associated molecular patterns[4] and initiating vascular inflammation. Therefore, the goal of this project is to examine the role of CKD-driven casp-1 activation in VSMC and CKD-related NH. We have established a CKD mouse model and published CKD-associated vascular remodeling. We exposed wild type and caspase-1 knockout mice to our CKD model, analyzed and quantified the NH lesion formed. We also examined in vitro and ex-vivo changes in VSMC-specific differentiation genes when exposed to uremic serum and cLDL, in the presence or absence of casp-1 inhibitor. We found that CKD serum induces with casp-1 activation and phenotypic changes in VSMCs from a “contractile” to a “synthetic” phenotype, which are reversed with casp-1 inhibition. In an ex-vivo model using relative quantification we found that VSMC contractile markers α -Actin, Calponin, SM-22, and Smoothelin gene expression of CKD mouse carotid VSMC were higher in casp-1 knockout mice when compared to wild-type (1.40, 1.28, 1.22, 1.41 respectively). Also using an in-vivo model, relative quantification of α-actin decreased from 1.0 to 0.329 when VSMCs were exposed to uremic serum and increased back to 0.588 when casp-1 inhibitor is added. The relative quantification of Calponin also decreased from 1.0 to 0.394 when exposed to uremic serum and increased back to 0.601 with caspa-1 inhibitor. We also found that casp-1 deficiency significantly reversed CKD-related vascular remodeling by reducing NH volume from 1,440,023.70 in wild-type mice to 71,069.97 μm2 in casp-1 knockouts (p-value 0.002). Our results provide a novel insight over the therapeutic potential of casp-1 inhibitors for CKD induced NH.