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Principal Investigator: David J Friedman
Organization: BETH ISRAEL DEACONESS MEDICAL CENTER
Fiscal Year: 2024
Award: $540,299
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
SUMMARY: Two ancestry-associated coding variants in APOL1 drive much of the racial disparity in rates of
kidney disease. However, the presence of two risk alleles (a high-risk genotype) does not lead to kidney disease
in all or even most individuals, indicating that other factors must also be important. Several environmental 2nd
hits have been identified such as HIV, therapeutic interferon, and Covid19. APOL1 itself is an innate immune
factor induced by interferons. A unifying theme is that both the APOL1 high-risk genotype and factors that elevate
APOL1 expression are required for development of APOL1 kidney disease. In addition to APOL1 protein function
as a membrane pore, APOL1 mRNA 3’-UTR has inversely oriented alu repeats that form a hairpin loop of double-
stranded RNA (dsRNA). This loop acts as an inflammatory factor because dsRNA is recognized by pattern
recognition receptors (PRR). Activation of PRR induces an anti-viral state with production of additional
interferons, which can trigger more APOL1 expression in a vicious cycle. Several mechanisms act as brakes on
APOL1 activity to prevent excess toxicity including transcript repression by miRNA and prevention of the PRR
inflammatory response by the A-to-I editing enzyme ADAR. We believe that imbalance between APOL1
activation and suppression may trigger kidney disease. To continue these studies, we will now: (1) Examine how
miRNA activity at the APOL1 3-’UTR regulates APOL1 expression. miRNA regulate gene expression by binding
to mRNA (usually 3’-UTR), promoting its degradation. We identified ~80 miRNAs in a high-throughput screen
with the potential to reduce APOL1 mRNA levels. We will perform a counterscreen to identify the most potent
miRNA at preventing APOL1 upregulation by interferons. We will find the intersection between miRNA expressed
in the podocyte and those that repress APOL1. We will test whether human polymorphisms in the APOL1 3’-
UTR alter miRNA binding and gene expression. We will validate the most relevant miRNA in vivo in APOL1 BAC
transgenic mice. (2) Characterize environmental and endogenous factors that induce or modify APOL1
expression. We will test a wide range of exogenous and endogenous molecules for their ability to induce APOL1
expression and to modulate cytokine-driven APOL1 expression. We will test the most potent molecules in APOL1
BAC transgenic mice. (3) Examine the role of APOL1 mRNA as an innate immune signaling molecule. We will
determine the specific PRR that recognize APOL1 3’-UTR dsRNA and whether that recognition and the resulting
inflammation depends on APOL1 genotype. We will assess how A-to-I editing of the APOL1 3’-UTR by ADAR
or protection by mRNA binding proteins may prevent the inflammatory loop driven by PRR recognition of APOL1
mRNA. We will test the effect of ADAR editing on the stability of the APOL1 mRNA and how A-to-I editing alters
3’-UTR binding by miRNA. Together, these experiments will help us understand the positive and negative factors
that regulate the interferon-driven APOL1 feed-forward inflammatory loop, APOL1 expression levels, and
podocyte injury leading to kidney disease.
Terms: <3' Untranslated Regions><3'UTR><AIDS Nephropathy><AIDS Virus><AIDS-Associated Nephropathy><AIDS-Related Nephropathy><Accounting><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Africa><African American group><African American individual><African American people><African American population><African Americans><African Sleeping Sickness><African Trypanosomiasis><African ancestry><African descent><Alleles><Allelomorphs><American><BAC clone><BACs><Bacterial Artificial Chromosomes><Binding><Binding Proteins><Biologic Models><Biological><Biological Models><COVID-19><CV-19><Caring><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Code><Coding System><Coronavirus Infectious Disease 2019><Development><Disparities><Disparity><Double-Stranded RNA><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Endogenous Factors><Environmental Factor><Environmental Risk Factor><Enzyme Gene><Enzymes><FSGS><Focal and Segmental Glomerulosclerosis><Focal segmental glomerular sclerosis><Frequencies><Gene Expression><Gene variant><Genes><Genetic Diseases><Genetic Polymorphism><Genotype><HIV><HIV-Associated Nephropathy><HIV-Related Nephropathy><Health><High Throughput Assay><Human><Human Immunodeficiency Virus-Associated Nephropathy><Human Immunodeficiency Viruses><Hypertension><IFN><IFN activation><Immune signaling><Immunity><Immunologic Factors><Immunological Factors><Individual><Inflammation><Inflammatory><Inflammatory Response><Injury><Interferon Activation><Interferons><Intracellular Communication and Signaling><Kidney><Kidney Diseases><Kidney Failure><Kidney Insufficiency><Kidney Urinary System><LAV-HTLV-III><Label><Lead><Ligand Binding Protein><Ligand Binding Protein Gene><Lymphadenopathy-Associated Virus><Membrane><Messenger RNA><Micro RNA><MicroRNAs><Model System><Modern Man><Molecular Interaction><Names><Nephropathy><Patients><Pattern Recognition><Pattern recognition receptor><Pb element><Persons><Phenotype><Prevention><Production><Protein Binding><Proteins><Proteinuria><Public Health><Renal Disease><Renal Failure><Renal Insufficiency><Reporter><Repression><Resistance><Risk><Risk Factors><Risk-associated variant><Role><Seminal><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Stimulus><System><Testing><Therapeutic><Toxic effect><Toxicities><Transcript><Transgenic Mice><UTRs><Untranslated Regions><Up-Regulation><Upregulation><Variant><Variation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Viral><Virus><Virus-HIV><Visceral Epithelial Cell><Work><allele variant><allelic variant><biologic><biological signal transduction><bound protein><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><counterscreen><cytokine><developmental><disparities in race><disparity due to race><dsRNA><environmental risk><experiment><experimental research><experimental study><experiments><genetic condition><genetic disorder><genetic variant><genomic variant><glomerular sclerosis><glomerular visceral epithelial cell><glomerulosclerosis><heavy metal Pb><heavy metal lead><high blood pressure><high risk><high throughput screening><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><immunologic substance><immunological substance><improved><in vivo><inequality due to race><inequity due to race><injuries><kidney disorder><mRNA><membrane structure><miRNA><miRNAs><mouse model><murine model><name><named><naming><podocyte><polymorphism><prevent><preventing><protein function><race based disparity><race based inequality><race based inequity><race disparity><race related disparity><race related inequality><race related inequity><racial disparities in health><racial disparity><racial health disparity><racial inequality><racial inequity><racially unequal><receptor binding><receptor bound><renal><renal disorder><resistant><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><sleeping sickness><social role>