Abstract: FR-OR031
Conserved Transcriptional Changes in Drosophila and Mouse Models of APOL1 Nephropathy
Session Information
- Genetically-Defined Kidney Diseases: From Variant Calling to Treatment
November 03, 2017 | Location: Room 392, Morial Convention Center
Abstract Time: 04:30 PM - 04:42 PM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- Han, Zhe, Children's National Health System, Washington, District of Columbia, United States
- Fu, Yulong, Children's National Health System, Washington, District of Columbia, United States
- Zhang, Peng, Children's National Health System, Washington, District of Columbia, United States
- Zhu, Jun-yi, Children's National Health System, Washington, District of Columbia, United States
Background
African Americans are at higher risk for developing chronic kidney diseases due to APOL1 risk alleles (RA), but the mechanism remains unclear. Expression of APOL1-RA in both the fly nephrocytes (a cell type similar to human podocytes) and the mouse podocytes led to cellular toxicity and renal disease phenotypes, but whether APOL1-RA induces similar transcriptional changes in kidney cells across different species is unknown.
Methods
We performed RNA-seq analysis for Drosophila nephrocytes with APOL1-G0, G1 or G2 expression, and compared the results with the recently published RNA-seq data from mouse kidney with induced expression of APOL1-G0, G1 or G2 in podocytes. Significant number of common target genes were identified. We characterized these genes into different groups based on molecular function and biological processes. Using the fly APOL1 model together with nephrocyte-specific gene knock down, we tested these common target genes of APOL1-RA for genetic interaction. We also examined the expression level changes of some common target genes in human patient samples.
Results
We found strikingly similar transcriptional profile changes in the genes that are dramatically up- or down-regulated from the RNA-seq analysis of the fly and mouse APOL1 nephropathy models. Among the significantly up-regulated genes in both fly nephrocytes and mouse podocytes are genes involved in gluconeogenesis, oxidation-reduction process, proton transport and cell adhesion. The most down-regulated common target genes are involved in glycogen biosynthesis, fatty acid metabolic process, cell trafficking, and mitochondria coenzymes. Genetic interaction assays demonstrated that knocking down of many common down-regulated genes in APOL1-RA expressing nephrocytes made the phenotype worse, whereas knocking down some of the up-regulated common target genes could partially rescue the nephrocyte phenotype caused by APOL1-RA. We found similar transcriptional changes for some common target genes in human APOL1 nephropathy patient samples.
Conclusion
Our findings suggest that the fly and mouse APOL1 nephropathy models share highly similar transcriptional profile changes, and some of these changes can be found in human patients, indicating conserved APOL1 toxicity mechanism in flies, mice and humans. We also showed that some common target genes of APOL1-RA could be used as potential therapeutic targets.
Funding
- NIDDK Support