Abstract: FR-PO139
Proteinuric Renal Injury Modulates Intestinal Lymphangiogenesis and Functionality of Plasma and Lymphatic HDL
Session Information
- Molecular Mechanisms of CKD - II
October 26, 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
- Otsuka, Tadashi, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Banan, Babak, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Kon, Valentina, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
Evidence suggests that in addition to plasma, critical changes in lipoprotein metabolism occur in the lymphatic circulation. Proteinuric renal injury changes lipoprotein levels and homoeostasis. Liver is a major regulator of lipoprotein metabolism, however, intestines also play a role, including synthesis of apolipoprotein AI (apoAI), the major protein in HDL. We examined how proteinuric renal injury affects intestinal handling of apoAI and functionality of HDL.
Methods
We studied Sprague-Dawley rats injected with puromycin aminonucleoside (PAN) or saline (C). Lymph was collected in conscious animals by indwelling mesenteric lymph duct cannulation. Lymphatic vessels were identified by immunohistochemistry (IHC) and RT-qPCR of podoplanin (PD). Functionality of HDL was assessed by cytokine response (TNFa, IL-6, Il-12 and iNOS/Arg1 ratio) in macrophages exposed to apoB-depleted HDL fractions isolated from plasma and lymph by RT-qPCR. HDL-cholesterol (HDL-C)/apoA1 ratio served as a HDL-particle size marker.
Results
PAN significantly increased urinary albumin creatinine ratio vs C. Intestines of PAN had significant increase in PD+lymphangiogenesis and enlargement of lacteals accompanied by higher mesenteric lymph flow (6.3±1.7 vs 0.8±0.4ml/h). VEGFA was significantly elevated in PAN lymph and plasma (2.8-fold and 2.2-fold, respectively). Plasma HDL of PAN caused significantly greater macrophage inflammatory response [TNFa, IL-6, Il-12 (3.5-fold, 5.1-fold, 6.4-fold, respectively)] vs C. By contrast, HDL from mesenteric lymph of PAN was not pro-inflammatory and rather significantly decreased iNOS/Arg1 vs controls (0.5-fold). Although PAN did not change intestinal expression of apoA1 mRNA and IHC showed lower ileal apoAI than C, hepatic apoAI mRNA expression was significantly higher (3.9-fold). However, total output of apoAI in mesenteric lymph (apoAI quantity over time) was significantly higher in PAN (59.4±24.7 vs 11.2±6.5μg/h). Although HDLC/apoA1 ratio in lymph was similar, this ratio doubled in plasma of PAN (129.2±45.2 vs 60.0±21.1).
Conclusion
PAN renal injury increases intestinal lymphangiogenesis, mesenteric flow, composition and functionality of lymphatic HDL which is distinct from functionality of plasma HDL.