# Modified Intestinal apoAI-particles and Lymphatics Accelerate CKD-driven CVD

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $432,500

## Abstract

Cardiovascular disease (CVD) has been linked to intestinal dysbiosis and chronic kidney disease,
(CKD) disrupts the intestinal epithelial integrity and disturbs carbohydrate and protein metabolism
that stimulate intestinal toxins. These toxins perpetuate the adverse effects through interorgan
crosstalk known as the kidney-gut-cardiovascular axis that involves blood vessels and nerves.
Our proposal challenges current research and clinical paradigms. We propose a new mediator
and pathway in the kidney-gut-cardiovascular axis. The pathogenic mediator in the axis is
intestinally-originating IsoLG-modified HDL. We hypothesize HDL, which is intestinally
synthesized or filtered from the circulation, becomes modified by intestinally-generated IsoLG.
The new pathway in the axis is the mesenteric lymphatic network that serves as a target and
perpetrator for IsoLG-HDL effects by increasing propulsive mobility in these vessels and activating
lymphatic endothelial cells. Together, the IsoLG-modified HDL and lymphatic vessels provide a
sustained influx of intestinally-derived accelerants promoting vascular dysfunction and the
development of atherosclerosis via the kidney-gut-cardiovascular axis. To test this hypothesis,
we propose three mechanistic aims. In Aim 1, we will test the hypothesis that CKD-induced
intestinal modification of HDL is a key pathogenic mechanism in the kidney-gut-cardiovascular
axis. First, we will define the impact of kidney disease and uremic toxins on intestinal IsoLG
production and modification of HDL. Next, we will use intestinal versus liver-specific knockouts of
apoAI, the main structure-function protein of HDL, and ascertain how CKD impacts the
contribution of intestinal- and plasma-derived HDL to the mesenteric lymph HDL pool. We will
then determine the specific IsoLG modifications of apoAI in the CKD setting. We will also define
the impact of CKD and IsoLG-modification on HDL-miRNA transport in plasma and mesenteric
lymph. In Aim 2, we will test the hypothesis that IsoLG-modified HDL disrupts the structure and
function of intestinal lymphatics in CKD. First, we will determine the impact of IsoLG-modified
HDL on LEC phenotypic changes, vessel integrity, contractility, and lymphangiogenesis in CKD.
We will then determine the role of HDL-miRNA in the interactions between HDL and the lymphatic
network. We will first identify miRNA carried by lymphatic HDL in CKD. Then, we will determine
the mesenteric lymphatic vascular network in humans with CKD and assess the link between
CKD-HDL and dysfunction of lymphatic vessels and lymphatic endothelial cells. In Aim 3, we will
test the hypothesis that CKD-driven acceleration in atherosclerosis can be reduced by IsoLG
scavengers that lessen intestinal IsoLG-adducted lipoproteins and lymphatic dysfunction.

## Key facts

- **NIH application ID:** 10089341
- **Project number:** 2P01HL116263-06A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** VALENTINA KON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,500
- **Award type:** 2
- **Project period:** 2014-06-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089341

## Citation

> US National Institutes of Health, RePORTER application 10089341, Modified Intestinal apoAI-particles and Lymphatics Accelerate CKD-driven CVD (2P01HL116263-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10089341. Licensed CC0.

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