The relationship between NRLP3 inflammasome and glycolytic metabolism of tubular epithelial cells in the development of renal fibrosis

Abstract

Renal fibrosis is a progressive detrimental connective tissue deposition on the kidney parenchyma, leading inevitably to renal function deterioration, dialysis dependence, and, ultimately, kidney transplantation. Despite accumulating knowledge of pathways and molecules involved in the fibrogenesis, little is known about which cellular mechanisms orchestrate this process. Recently, new evidences reveal that altered glycolytic and oxidative metabolisms of proximal tubular epithelial cells (PTECs) are intimately involved in the renal fibrotic process. NRLP3 inflammasome is a multiprotein platform that connects inflammatory pathways and metabolic changes. Based on that, our hypothesis is that metabolic changes are the common pathway of proinflammatory stimuli sensed by NLRP3 inflammasome and the development of fibrosis. PTECs will be isolated from wild type and NRLP3 knockout mice aiming to study the role of NRLP3 inflammasome in the cellular energetic metabolism in the presence of uric acid and TGF-b using different techniques, such as Seahorse, Western blotting, flow cytometry and CHIP-PCR. In addition to vitro experiments, the project includes experimental models of unilateral ureter obstruction in wild type and knockout mice aiming to evaluate the role of NRLP3 and metabolism-related factors in the onset and development of kidney disease.