Chronic kidney disease, regardless of etiology, is characterized by a relentless progression of fibrosis that gradually destroys the normal architecture. Many parallels have been drawn between atherogenesis and the pathogenic mechanisms that cause progressive kidney destruction by fibrosis. The purpose of this application is to further define key pathways in kidney fibrosis, particularly the functional relationship between ligands and their receptor in the progression of fibrosis. Our studies thus far demonstrate that oxidized lipoproteins, the pathologic component of atherosclerotic lesions, promote fibrogenic pathways in the kidney during chronic injury. CD36 is one of the major scavenger receptors responsible for uptake of oxidized lipoproteins. We recently demonstrated that the severity of fibrosis was significantly attenuated in CD36-deficient mice during chronic injury by obstruction by decreasing oxidative stress and reducing activation of pro-inflammatory pathways. We hypothesize that CD36- expressing macrophages and renal tubular epithelial cells activates cell-specific pro- inflammatory and oxidative pathways through interaction with its ligand oxidized lipoprotein. The studies outlined in this proposal continue the line of investigation in the original K08 and will focus on: (1) defining the major oxidant pathways modulated by CD36 during chronic injury using gas chromatography and mass spectrometry, as well as elucidating the inflammatory pathways activated by CD36;(2) differentiating macrophage-dependent and tubular epithelial cell-dependent effects of CD36 through the generation of chimeric mice with bone marrow transplantation and in vitro models;and (3) extending investigation of the role of CD36 in chronic kidney injury by proteinuria, a model more akin to human renal disease. These studies will improve our understanding of the key cellular receptors and the pathways they mediate in the progression of renal fibrosis. This research will continue to prepare the applicant for an academic career as an independent investigator in the field of kidney fibrogenesis.
The number of patients with chronic kidney disease and end-stage renal disease is increasing at an alarming rate with few therapeutic interventions to halt or reverse fibrosis in human kidneys that are chronically damaged. Our studies on the cellular receptor CD36 and its ligand oxidized lipoprotein will shed new light in the progression of chronic kidney failure with hopes of developing new innovative therapies to alter its natural progression.
| Pennathur, Subramaniam; Pasichnyk, Katie; Bahrami, Nadia M et al. (2015) The macrophage phagocytic receptor CD36 promotes fibrogenic pathways on removal of apoptotic cells during chronic kidney injury. Am J Pathol 185:2232-45 |
| Eddy, Allison A; López-Guisa, Jesús M; Okamura, Daryl M et al. (2012) Investigating mechanisms of chronic kidney disease in mouse models. Pediatr Nephrol 27:1233-47 |
