# Apolipoprotein L1 Interaction with SNARE Proteins in the Pathogenesis of Chronic Kidney Disease

> **NIH NIH K08** · OHIO STATE UNIVERSITY · 2021 · $160,920

## Abstract

Summary
Chronic kidney diseases (CKDs) are a major public health problem affecting more than 20 million people in the
United States. African Americans are disproportionately affected by progressive CKDs, especially focal
segmental glomerulosclerosis (FSGS). Genetic variants in the carboxy-terminal domain of APOL1 are
associated with FSGS and other non-diabetic CKDs in populations with African ancestry. These variants change
the amino acid sequence of APOL1 and explain much of this increased risk for CKDs in these populations. The
pathogenetic mechanisms that lead from these APOL1 variants to CKD are not known. The carboxy-terminus of
APOL1 interacted with VAMP8, an endosomal/lysosomal SNARE protein involved in vesicular trafficking and
APOL1 kidney disease-associated variants attenuated the interaction with VAMP8 secondary to protein
conformational changes induced by the variants. Like SNARE proteins, APOL1 localized to vesicular structures
in the podocytes of the healthy human kidney. We hypothesize that APOL1:SNARE interaction is necessary to
mitigate/attenuate podocyte stress response, and APOL1 variants disrupt functional SNARE interaction and
mediate cytotoxicity.
To test this hypothesis, we propose the following aims:
First, we will use stable cell lines expressing APOL1 and healthy human kidneys to identify additional interacting
SNARE proteins. We will use live-cell confocal microscopy to track APOL1:SNARE localization in various
subcellular compartments in the presence and absence of immune stimuli.
Second, we will investigate the cytotoxicity of reference and variant APOL1 proteins in the absence and presence
of immune stimuli and reference APOL1 in the absence and presence of SNARE knockdown in cell culture
models.
Through these aims, I will obtain biochemical, imaging and proteomics data necessary to address our long term
goal of identifying agents for the treatment of APOL1-associated kidney diseases. Understanding the molecular
mechanisms by which APOL1 variants cause proteinuric CKD is essential for the development of new
therapeutic strategies. I propose to use imaging and proteomics tools to study the pathological effects of APOL1
variants on its function and to learn bioinformatics tools to allow me to develop models to investigate CKD
mechanisms. As a young physician-scientist, this project will help me to acquire new skills and knowledge while
studying an important public health problem that afflicts my patients.

## Key facts

- **NIH application ID:** 10206131
- **Project number:** 5K08DK123411-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Sethu Madhavan Madhavan
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $160,920
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206131

## Citation

> US National Institutes of Health, RePORTER application 10206131, Apolipoprotein L1 Interaction with SNARE Proteins in the Pathogenesis of Chronic Kidney Disease (5K08DK123411-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10206131. Licensed CC0.

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