Despite the efficacy of combined anti-retroviral therapy (cART) in control of HIV infection, chronic, progressive kidney disease (CKD) causes significant morbidity in HIV patients. HIV-associated nephropathy (HIVAN) and focal segmental glomerulosclerosis (FSGS) remain the most prevalent pathological diagnoses in biopsies from HIV patients with CKD in contemporary cohorts. In the U.S., almost 90% of HIV infected subjects with CKD are African American. A landmark discovery associated genetic variation in the APOL1 gene with excess prevalence of advanced, non-diabetic CKD in African Americans, with published odds ratios for a recessive model of disease of 29 for HIVAN and 17 for primary FSGS. Not only do APOL1 risk genotypes independently accelerate CKD progression, subjects with APOL1 risk genotype and CKD do not benefit from current treatment. Although APOL1 kidney disease-associated variants are common (12% of African Americans carry the risk genotype), only a subset of these individuals develop advanced CKD, consistent with a second hit to initiate disease. Our prior studies established a requirement for direct HIV-1 infection of kidney cells in HIVAN pathogenesis, indicating HIV is a model second hit. The biological mechanisms driving the association of APOL1 variants with CKD in African Americans are unknown. Studies published by us and other groups suggest APOL1 expressed in kidney cells mediates disease. Since APOL1 is a gene unique to humans and some primates, we have generated mouse models and cultured podocytes from urine of subjects with APOL1 risk genotypes to discover and model the mechanisms by which HIV-1 infection triggers CKD in susceptible individuals. These tools overcome the limited availability of human samples to test the following hypothesis: APOL1 has an endogenous function in the glomerular podocyte that is necessary to resist environmental stress and maintain podocyte health and these pathways are dysregulated in the presence of two risk variants where clinical disease manifests with the introduction of an environmental stress. We propose two specific aims to identify pathogenic pathways the mediate APOL1-associated kidney diseases:
Aim 1 : Use comparative genomics to identify candidate pathways mediating APOL1-associated kidney (podocyte) diseases.
Aim 2 : Use HIV-1 infection as a model trigger to characterize pathways mediating APOL1 regulated defenses to a CKD-inducing second hit to the podocyte. While focused on the APOL1 variant-HIV interactions, these causal pathways may identify mechanisms shared with other APOL1-associated CKDs. Our group is ideally positioned to undertake these studies, including established experts in HIVAN pathogenesis, genetics of chronic kidney disease in African Americans, and state-of-the-art genomic analysis. Understanding the mechanisms by which variant APOL1 associates with CKD is one of the most compelling questions in biomedical science, and these studies could potentially produce data that drives development of novel diagnostics and treatments for CKD in African Americans.

Public Health Relevance

Kidney disease is an increasing chronic complication in the aging HIV positive individuals. HIV-associated nephropathy (HIVAN) is a particularly aggressive chronic kidney disease (CKD) that continues to be clinically relevant in sub-optimally treated HIV positive populations worldwide. Recent genetic studies have identified changes (variations) in a single gene (APOL1) that are strongly linked with HIVAN. The goal of this project is to understand how APOL1 functions in kidney cells, and how in the setting of HIV-1 infection, variations in APOL1 cause CKD. Understanding the connection between APOL1 and CKD could produce diagnostics and treatments to reduce major causes of CKD in African Americans in addition to HIVAN.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK108329-01
Application #
9045218
Study Section
Special Emphasis Panel (ZDK1-GRB-G (O3))
Program Officer
Kimmel, Paul
Project Start
2015-09-21
Project End
2020-06-30
Budget Start
2015-09-21
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$414,218
Indirect Cost
$144,398
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Bruggeman, Leslie A; O'Toole, John F; Sedor, John R (2017) Identifying the Intracellular Function of APOL1. J Am Soc Nephrol 28:1008-1011
O'Toole, John F; Bruggeman, Leslie A; Sedor, John R (2017) APOL1 and Proteinuria in the AASK: Unraveling the Pathobiology of APOL1. Clin J Am Soc Nephrol 12:1723-1725
Madhavan, Sethu M; O'Toole, John F; Konieczkowski, Martha et al. (2017) APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8. JCI Insight 2:
O'Toole, John F; Bruggeman, Leslie A; Madhavan, Sethu et al. (2017) The Cell Biology of APOL1. Semin Nephrol 37:538-545
Bruggeman, Leslie A (2017) HIV-1 Infection of Renal Cells in HIV-Associated Nephropathy. J Am Soc Nephrol 28:719-721