# Macrophages and attenuation of inflammation resolution in APOL1 nephropathy

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $589,566

## Abstract

PROJECT SUMMARY
Individuals who self-identify as Black in the United States experience disproportionately higher rates of
developing chronic kidney disease (CKD) and experiencing CKD progression to end-stage kidney disease
(ESKD). A portion of this health difference is not explained by socioeconomic and traditional risk factors,
necessitating the study of other biological factors contributing to disease pathogenesis. Human genetics studies
have identified and validated two common coding variants in the primate-specific Apolipoprotein L1 (APOL1)
gene that contribute to high rates of proteinuric CKD in patients with African ancestry. These alleles, termed G1
and G2, evolved and became common due to the survival advantage they confer against African
trypanosomiasis. Despite their role in primate innate immunity, not much is known about the role immune cells
such as macrophages, which contribute to kidney injury and repair, play in APOL1 nephropathy.
To address this gap, we propose to use genome-edited induced pluripotent stem cell (iPSC) derived
macrophages and transgenic mice to investigate how G1 and G2 APOL1 alter macrophage function to promote
kidney disease. We focus on the macrophage due to its dual role in innate immune responses to pathogens and
contribution to kidney injury and fibrosis. In preliminary studies, we have generated genome-edited G1 iPSCs
sharing an isogenic background with G0 controls and found that G1 iPSC derived macrophages maintain higher
expression of proinflammatory genes under multiple conditions. Because chronic sterile macrophage
inflammation can drive kidney disease, we are investigating mechanisms by which G1 and G2 APOL1 promote
a sustained proinflammatory macrophage phenotype and maladaptive tissue repair. In various complex diseases
including CKD, resolution of tissue inflammation requires anti-inflammatory reprogramming of immune cells and
clearance of apoptotic cells by macrophages via efferocytosis. Additionally, macrophage inflammation can be
induced by stress or dysfunction of the endoplasmic reticulum (ER), which has been implicated in APOL1 biology
in other cell types. Therefore, we hypothesize that G1 and G2 macrophages undergo impaired anti-inflammatory
reprogramming and inefficient efferocytosis through enhanced ER stress, thereby contributing to non-resolving
kidney inflammation and APOL1 nephropathy. To test this central hypothesis, we will delineate which ER stress
pathways G1 and G2 APOL1 perturb (Aim 1), investigate anti-inflammatory signaling and mitochondrial
dysfunction in the attenuation of reparative reprogramming of G1 and G2 macrophages (Aim 2), and determine
the mechanisms by which G1 and G2 APOL1 impair efferocytosis (Aim 3). The proposed investigations will test
a novel hypothesis that APOL1 risk alleles amplify kidney injury through macrophage dysfunction. Elucidating
the macrophage’s role in APOL1 nephropathy will offer critical insight for developing complementary strategies
to treat A...

## Key facts

- **NIH application ID:** 10820548
- **Project number:** 5R01DK131521-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jennie J LIn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $589,566
- **Award type:** 5
- **Project period:** 2022-05-20 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820548

## Citation

> US National Institutes of Health, RePORTER application 10820548, Macrophages and attenuation of inflammation resolution in APOL1 nephropathy (5R01DK131521-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10820548. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*