Lipoprotein Modulation of Proteinuric Renal Injury

High density lipoprotein (HDL) and its main protein, apolipoprotein AI (apoAI), have established benefits in various cells, but whether these cytoprotective effects of HDL pertain in renal cells is unclear. We investigated the in vitro consequences of exposing damaged podocytes to normal apoAI, HDL, apoAI mimetic (L-4F) and in vivo effects of L-4F on kidney and atherosclerotic injury in a podocyte-specific injury model of proteinuria. In vitro, primary mouse podocytes were injured by puromycin aminonucleoside (PAN). Cellular viability, migration, production of reactive oxygen species (ROS), apoptosis and the underlying signaling pathway were assessed. In vivo, we used a proteinuric model, Nphs1-hCD25 transgenic (NEP25(+)) mice, which express human CD25 on podocytes, and podocyte injury can be induced by immunotoxin (LMB2) and generated a proteinuric atherosclerosis model, NEP25(+):apoE−/− mice, by mating apoE-deficient (apoE−/−) mice with NEP25(+) mice. Animals received L-4F or control vehicle. Renal function, podocyte injury and atherosclerosis were assessed. PAN reduced podocyte viability, migration and increased ROS production, all significantly lessened by apoAI, HDL and L-4F. L-4F attenuated podocyte apoptosis and diminished PAN-induced inactivation of Janus family protein kinase-2/ signal transducers and activators of transcription 3. In NEP25(+) mice, L-4F significantly lessened overall proteinuria, and preserved podocyte expression of synaptopodin and cell density. Proteinuric NEP25(+):apoE−/− mice had more atherosclerosis than non- proteinuric apoE−/− mice and these lesions were significantly decreased by L-4F. Normal human apoAI, HDL and apoAI mimetic protect against podocyte damage. ApoAI mimetic provides in vivo beneficial effects on podocytes that culminate in reduced albuminuria and atherosclerosis. The results suggest supplemental apoAI/apoAI mimetic may be novel candidates to lessen podocyte damage and its complications.