Kidney Week

Abstract: TH-PO936

Scavenging Reactive Dicarbonyls Improves Renal Injury: Role of Urinary Isolevuglandin-Modified Lipoproteins and Renal Lymphangiogenesis

Session Information

• Molecular Mechanisms of CKD - I
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Zhong, Jianyong, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Jianyong Zhong,

• Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Haichun Yang,

• Matsusaka, Taiji, Tokai University School of Medicine, Isehara, KANAGAWA, Japan

Taiji Matsusaka,

• Fogo, Agnes B., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Agnes B. Fogo,

• Linton, Macrae F., Vanderbilt University School of Medicine, Nashville, Tennessee, United States

Macrae F. Linton,

• Kon, Valentina, Vanderbilt University, Nashville, Tennessee, United States

Valentina Kon,

• Davies, Sean Stephen, Vanderbilt University, Nashville, Tennessee, United States

Sean Stephen Davies,

Background

The kidney has a well-developed lymphatic system and lymphangiogenesis occurs in diseased kidney. Our previous studies revealed that proteinuric injury increases urinary lipoproteins which were recently shown to regulate lymphangiogenesis. Isolevuglandins (IsoLG) and related reactive dicarbonyls are lipoxidation products that can modify lipoproteins and degrade their functions. We determined if scavenging dicarbonyls, including IsoLG that block protein modification, can modulate renal lymphangiogenesis and lessen renal injury.

Methods

Nphs1-hCD25 mice (Nep25) expressing podocyte-specific human CD25 become proteinuric after injection of immunotoxin (LMB2). Nep25 mice were treated with the dicarbonyl scavenger, PPM (1g/L) or vehicle from 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 in lymphatic endothelial cells (LEC).

Results

After LMB2 injection, Nep25 mice had significantly higher urinary ACR (32-fold), KIM-1 (35-fold), urinary apoAI (7.3-fold), and IsoLG-protein adduct excretion (1.3-fold). Proteinuric kidneys showed greater immunostaining for apoAI and a denser lymphatic vessel network (podoplanin staining: 2.1-fold). In vitro, IsoLG-apoAI increased LEC viability (1.6-fold) and migration (1.1-fold) vs unmodified apoAI. These effects were significantly abrogated by exposure to PPM. In vivo, proteinuric Nep25 mice treated with PPM showed reduced lymphangiogenesis (podoplanin: 0.7-fold and LYVE-1: 0.5-fold). PPM treatment also significantly reduced ACR (0.8-fold), urinary KIM-1 (0.7-fold) together with significant reduction in IsoLG excretion (0.4-fold).

Conclusion

We conclude that dicarbonyl scavenger PPM lessens proteinuric renal damage through mechanisms that include preserving lymphatic endothelial cell functionality and diminishing urinary lipoprotein-stimulated renal lymphangiogenesis.

Funding

• Other NIH Support