African American have an approximately 3-5 fold increased risk of developing end stage renal disease. Recently, coding region polymorphisms (G1 and G2) in the apolipoprotein L1 (APOL1) gene has been identified that can explain this increased risk. According to recent reports, there are more than 3 million African Americans with high-risk genotype, who are at increased risk for kidney disease development. Interestingly, mutations of APOL1 can present with diverse phenotypes, including patients with hypertensive nephrosclerosis (HN) presenting with low-grade albuminuria or patients with focal segmental glomerulosclerosis (FSGS) and HIV associated renal disease (HIVAN) showing nephrotic syndrome. APOL1 is an HDL associated protein in the circulation, but glomerular and tubule epithelial cells, endothelial cells and vascular smooth muscle cells also express APOL1. APOL1 is a relatively recent gene and it is not present in rodents. Animal model studies proving that APOL1 is the causal gene for kidney disease development is lacking.
The aim of the proposal is to understand APOL1-Associated Kidney Disease (AAKD) development.
Aim1. A. Provide decisive evidence that APOL1 risk variants compared to the reference allele cause kidney disease B. Demonstrate that our cell type specific inducible mouse model system recapitulates human disease at a functional, histological and molecular level. C. Determine the critical cell type(s) for APOL1-mediated disease development by characterizing the phenotype of transgenic mice with podocyte, tubule epithelial cell, liver, endothelial and vascular smooth muscle specific inducible G0, G1 and G2 APOL1 expression.
Aim2. Define whether lowering risk allele APOL1 levels can stabilize or reverse kidney disease Aim3. Understand the transcriptional regulation of APOL1 in podocytes Examine whether transcriptional suppression of APOL1 by STAT inhibitors can reduce APOL1 expression and ameliorate the mutant protein induced cytotoxicity. The studies shall have a broad significance, as APOL1 mutations might be the most common genetic cause of glomerulosclerosis; including FSGS.

Public Health Relevance

African American have an approximately 3-5 fold increased risk of developing end stage renal disease. Recently, coding region polymorphisms in the apolipoprotein L1 (APOL1) gene has been identified that can explain this increased risk. The current proposal aims to examine the mechanism of APOL1 associated kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK105821-05
Application #
9872159
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Parsa, Afshin
Project Start
2015-12-21
Project End
2020-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Qiu, Chengxiang; Huang, Shizheng; Park, Jihwan et al. (2018) Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease. Nat Med 24:1721-1731
Park, Jihwan; Shrestha, Rojesh; Qiu, Chengxiang et al. (2018) Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758-763
Scerbo, Diego; Son, Ni-Huiping; Sirwi, Alaa et al. (2017) Kidney triglyceride accumulation in the fasted mouse is dependent upon serum free fatty acids. J Lipid Res 58:1132-1142
Beckerman, Pazit; Bi-Karchin, Jing; Park, Ae Seo Deok et al. (2017) Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat Med 23:429-438
Heymann, Jurgen; Winkler, Cheryl A; Hoek, Maarten et al. (2017) Therapeutics for APOL1 nephropathies: putting out the fire in the podocyte. Nephrol Dial Transplant 32:i65-i70
Bajaj, Archna; Susztak, Katalin; Damrauer, Scott M (2017) APOL1 and Cardiovascular Disease: A Story in Evolution. Arterioscler Thromb Vasc Biol 37:1587-1589
Edeling, Maria; Ragi, Grace; Huang, Shizheng et al. (2016) Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog. Nat Rev Nephrol 12:426-39
Huang, Shizheng; Susztak, Katalin (2016) Epithelial Plasticity versus EMT in Kidney Fibrosis. Trends Mol Med 22:4-6
Reiner, Alex P; Susztak, Katalin (2016) APOL1 Variants: From Parasites to Kidney Function to Cardiovascular Disease. Arterioscler Thromb Vasc Biol 36:219-20

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