# Hypertension and glomerular injury in hyperhomocysteinemia - role of inflammatory exosomes

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $500,354

## Abstract

Over the last five years, we have demonstrated that the activation of NOD-like receptor protein with pryin domain
containing 3 (NLRP3) inflammasomes in podocytes triggers and promotes glomerular dysfunction and sclerosis
during hyperhomocysteinemia (hHcy). Given that the NLRP3 inflammasomes are activated primarily in the
cytosol, their products such as IL-1β, IL-18 or high mobility group protein B1 (HMGB1) may not be secreted out
of cells via a classical and Golgi apparatus-mediated delivery pathway. It is now imperative to address how
NLRP3 activation-derived products are released out of podocytes to trigger the inflammatory response leading
to injury in glomeruli. Our preliminary studies have shown that homocysteine (Hcy) stimulation or hHcy not only
resulted in NLRP3 inflammasome activation within podocytes, but also increased the release of exosomes that
are enriched with NLRP3 inflammasome products. Lysosomal acid sphingomyelinase (ASM) activation was
importantly involved in hHcy-induced lysosome dysfunction, which reduced the degradation of multivesicular
body (MVB) resulting in robust exosome secretion. We therefore hypothesize that an exosome secretory
mechanism mediated by lysosomal ASM-ceramide signaling pathway is concurrently activated with NLRP3
inflammasomes in podocytes during hHcy and both work in concert to trigger or promote local inflammatory
response, leading to glomerular injury and sclerosis. To test this hypothesis, three Specific Aims are proposed.
Specific Aim 1 will determine whether lysosomal ASM-ceramide signaling pathway contributes to NLRP3
inflammasome activation and enhanced release of inflammatory exosomes in podocytes during hHcy, which
together trigger local glomerular inflammation, injury and even sclerosis using Smpd1-/- mice, podocyte-specific
Smpd1 transgenic mice (Smpd1trg/PodoCre), and their wild type littermates (WT/WT and Smpd1trg/Podowt).
Specific Aim 2 will determine whether Hcy in vitro or hHcy in vivo stimulates the formation of MVBs containing
NRLP3 inflammasome products in podocytes to release inflammatory exosomes and whether these inflamed
exosomes induce glomerular dysfunction and injury. Specific Aim 3 will explore the molecular mechanisms by
which lysosome trafficking and interactions with MVBs are altered upon Hcy stimulation to prolong the fate of
MVBs, thereby promoting robust release of inflammatory exosomes in primary cultures of podocytes or glomeruli
from Smpd1-/- and Smpd1trg/PodoCre mice and their wild type littermates. These proposed studies represent the
first effort in the field to link the activation of NLRP3 inflammasomes in podocytes to the instigation of glomerular
inflammatory response and injury. The findings may lead to a paradigm shift in how we understand the molecular
mechanisms of glomerular inflammation during hHcy and in how to develop new therapeutic strategies to
mechanistically counteract glomerular injury or end-stage renal disease during hHcy.

## Key facts

- **NIH application ID:** 10180943
- **Project number:** 5R01DK054927-22
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** PinLan Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $500,354
- **Award type:** 5
- **Project period:** 1998-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180943

## Citation

> US National Institutes of Health, RePORTER application 10180943, Hypertension and glomerular injury in hyperhomocysteinemia - role of inflammatory exosomes (5R01DK054927-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10180943. Licensed CC0.

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