Lessons From APOL1 Animal Models

Teruhiko Yoshida,Khun Zaw Latt,Jeffrey B Kopp,Jurgen Heymann

doi:10.3389/fmed.2021.762901

Abstract

African-Americans have a three-fold higher rate of chronic kidney disease compared to European-Americans. Much of this excess risk is attributed to genetic variants in APOL1, encoding apolipoprotein L1, that are present only in individuals with sub-Saharan ancestry. Although 10 years have passed since the discovery of APOL1 renal risk variants, the mechanisms by which APOL1 risk allele gene products damage glomerular cells remain incompletely understood. Many mechanisms have been reported in cell culture models, but few have been demonstrated to be active in transgenic models. In this narrative review, we will review existing APOL1 transgenic models, from flies to fish to mice; discuss findings and limitations from studies; and consider future research directions.

Highlights

APOL1 genetic variants are an important cause of kidney disease, affecting individuals who have sub-Saharan African ancestry [1]
When African trypanosomes circulating in blood ingest HDL particles, APOL1 is released from the HDL particles and trafficked to the lysosomes where it forms ion channels, thereby killing the parasite and preventing African sleeping sickness
APOL1-mediated cytotoxicity is prominent in podocytes

Summary

INTRODUCTION

APOL1 genetic variants are an important cause of kidney disease, affecting individuals who have sub-Saharan African ancestry [1]. Bruggeman et al [24] studied the well-characterized Tg26 model of HIVassociated nephropathy, in which the presence of the six regulatory and accessory genes of HIV-1, under the control of viral long terminal repeats (LTR), develop FSGS and/or collapsing glomerulopathy [25] They reported that among Nphs.APOL1 × Tg26 dual transgenic mice, APOL1-G0 × Tg26 mice showed less podocyte loss in compared with APOL1G2 × Tg26 or Tg26 mice alone [24]. The authors suggested that APOL1 risk variant expression increases the susceptibility to lipidmediated podocyte injury, leading to mitochondrial dysfunction Another injury pathway was identified by Wakashin et al, who reported on a CAG-APOL1-B3 mouse model expressing the APOL1-B3 protein isoform under control of a CMV early enhancer/chicken β-actin promoter. These effects are more severe than those seen in humans, perhaps due to higher expression levels in the flies or TABLE 1 | Summary of APOL1 animal models

Findings

DISCUSSION

Background

Findings From Animal Models