Single-Cell Transcriptional Signatures of Glomerular Disease in Transgenic Mice with APOL1 Variants

Author:

Yoshida Teruhiko1ORCID,Latt Khun Zaw1ORCID,Santo Briana A.2,Shrivastav Shashi1,Zhao Yongmei3ORCID,Fenaroli Paride45,Chung Joon-Yong6ORCID,Hewitt Stephen M.6,Tutino Vincent M.2,Sarder Pinaki27ORCID,Rosenberg Avi Z.4ORCID,Winkler Cheryl A.3ORCID,Kopp Jeffrey B.1ORCID

Affiliation:

1. Kidney Disease Section, Kidney Diseases Branch, NIDDK, NIH, Bethesda, Maryland

2. Department of Pathology and Anatomical Sciences, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, New York

3. Frederick National Laboratory for Cancer Research, NCI, NIH, Frederick, Maryland

4. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland

5. S.C. Nefrologia e Dialisi, AUSL-IRCCS, Reggio Emilia, Italy

6. Center for Cancer Research, NCI, NIH, Bethesda, Maryland

7. College of Medicine, University of Florida, Gainesville, Florida

Abstract

Key Points Apolipoprotein L1 (APOL1)-G1 induced kidney disease in the two APOL1 transgenic mouse models, HIV-associated nephropathy and IFN-γ administration.Glomerular single-nuclear RNA-sequencing identified genes differentially expressed among mice with APOL1-G1 and G0 variants at single-cell resolution. Background Apolipoprotein L1 (APOL1) high-risk variants contribute to kidney disease among individuals with African ancestry. We sought to describe cell-specific APOL1 variant–induced pathways using two mouse models. Methods We characterized bacterial artificial chromosome/APOL1 transgenic mice crossed with HIV-associated nephropathy (HIVAN) Tg26 mice and bacterial artificial chromosome/APOL1 transgenic mice given IFN-γ. Results Both mouse models showed more severe glomerular disease in APOL1-G1 compared with APOL1-G0 mice. Synergistic podocyte-damaging pathways activated by APOL1-G1 and by the HIV transgene were identified by glomerular bulk RNA sequencing (RNA-seq) of HIVAN model. Single-nuclear RNA-seq revealed podocyte-specific patterns of differentially expressed genes as a function of APOL1 alleles. Shared activated pathways, for example, mammalian target of rapamycin, and differentially expressed genes, for example, Ccn2, in podocytes in both models suggest novel markers of APOL1-associated kidney disease. HIVAN mouse-model podocyte single-nuclear RNA-seq data showed similarity to human focal segmental glomerulosclerosis glomerular RNA-seq data. Differential effects of the APOL1-G1 variant on the eukaryotic initiation factor 2 pathway highlighted differences between the two models. Conclusions These findings in two mouse models demonstrated both shared and distinct cell type–specific transcriptomic signatures induced by APOL1 variants. These findings suggest novel therapeutic opportunities for APOL1 glomerulopathies.

Funder

National Institute of Diabetes and Digestive and Kidney Diseases

National Cancer Institute

Publisher

Ovid Technologies (Wolters Kluwer Health)

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