Abstract 353: Aldehyde Scavenging Reduces Renal Injury Role of IsoLG-modified apoAI

Abstract

Reactive aldehydes, including isolevuglandins (IsoLG) are lipoxidation products that can modify lipoproteins and promote cellular dysfunction. Previously, we showed that proteinuric injury increases urinary apoAI and causes renal lymphangiogenesis. We now investigate the role of IsoLG and effects of IsoLG scavenging on renal injury and lymphatics. Nphs1-hCD25 mice (NEP25) expressing podocyte-specific human CD25 become proteinuric after injection of immunotoxin (LMB2). NEP25 mice were treated with the aldehyde scavenger, PPM (1g/L) or vehicle from the onset of proteinuria until sacrifice (2 weeks). We assessed proteinuria [measured as albumin:creatinine ratio (ACR)], urinary apoAI, IsoLG, KIM-1 (marker of tubular injury), and the renal expression of lymphatic markers (LYVE-1 and podoplanin). In vitro , we assessed the effects of apoAI or modified apoAI (IsoLG-apoAI) +/- PPM on proximal tubular cells (PTC) and lymphatic endothelial cells (LEC). As expected, LMB2 significantly increased ACR and urinary KIM-1. Proteinuric injury also significantly increased urinary IsoLG (262%). Similar to our previous data, proteinuric kidneys increased expression of apoAI, VEGF-C, podoplanin and LYVE-1 compared to wild type mice. In vitro , PTC uptake of IsoLG-apoAI was significantly increased (39%), an effect that was abrogated by exposure to PPM (22%). In LECs, compared to apoAI, IsoLG-apoAI significantly increased viability (27%) and migration (13%), effects that were abrogated by exposure to PPM. In vivo , proteinuric NEP25 mice treated with PPM showed significantly reduced ACR (22%), urinary KIM-1 (30%) and IsoLG excretion (64%). We conclude that aldehyde scavenger lessens proteinuric renal damage through mechanisms that include reducing proximal tubule uptake of IsoLG-modified apoAI and preserving lymphatic endothelial cell functionality.