# Modelling mechanisms of progressive chronic kidney disease in APOL1 high-risk live-donors using BAC-Transgenic mice

> **NIH NIH R21** · YALE UNIVERSITY · 2024 · $209,375

## Abstract

Technical Abstract
Americans with African ancestry (AAs) make up 12-15% of the US population, but account for
35% of ESKD. This disparity is partly attributed to the carriage of exonic variants in APOL1 (G1,
G2 risk alleles) within AAs, while all ancestries carry the major allele (G0). Only 10-15% with risk-
genotype develop progressive CKD, suggesting “second hits” are needed. In kidney
transplantation, the risk of progressive CKD in living donors (LDs) is a vital concern. Compared
to white LDs, AA-LDs have a higher risk of CKD/ESKD along with increased risks of hypertension
and inflammatory glomerulonephritis. Since the identification of APOL1-G1/G2 risk-genotypes,
whether and how risk-genotype among AA-LDs contributes to the observed increased post-
donation ESKD risk in AAs has remained a central question. In human LDs, significantly long
follow-up times will be needed to understand actual donation-attributable risk with APOL1-variants.
In light of these data, delineating the “second or third hits” that would modify disease risk in LDs
with APOL1 risk-genotype, needs examination using a suitable model system. Here, we take
advantage of our human BAC transgenic mice (BAC-Tg) expressing physiologic levels of APOL1
G0, G1, or G2 which we identify as recapitulating observed human immunologic and kidney
phenotypes including CKD. We perform unilateral nephrectomy to model live donation, and
specifically examine two putative second hit phenomena. In aim-1, we will test the hypothesis that
nephrectomized G1- and G2- BAC-Tg develop hypertension-related progression of CKD. To
induce hypertension in our mice, we will use models of dietary salt-loading, and also test sodium
restriction as a therapeutic strategy. Detailed hemodynamic and histo-morphometric studies will
provide mechanistic insight in this aim. Based on our recent identification of an immunologic role
for APOL1-G1 and G2 variants, in Aim-2 we will mimic systemic immune activation in
nephrectomized BAC-tg lines. Our goal here is to define the role and mechanism of Ifng-induced
glomerulopathy in APOL1 BAC transgenic mice post-nephrectomy using novel doxycycline-
inducible IFNG-expressing BAC-Tg lines. Novel Podocin rtTA TRAP mice will be utilized to
identify differentially expressed genes to identify mechanisms in the pathogenesis of APOL1-
induced FSGS, simultaneously comparing podocytes from uninephric and binephric mice.
This proposal combines an array of different skill sets and unique tools to address critically
important mechanistic and epidemiologic questions in transplantation, with the potential to reveal
novel therapeutics for APOL1 - a profoundly unmet need.

## Key facts

- **NIH application ID:** 10851925
- **Project number:** 5R21AI178705-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Shuta Ishibe
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851925

## Citation

> US National Institutes of Health, RePORTER application 10851925, Modelling mechanisms of progressive chronic kidney disease in APOL1 high-risk live-donors using BAC-Transgenic mice (5R21AI178705-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10851925. Licensed CC0.

---

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