From Gene to Clinic: The Role of APOL1 in Focal Segmental Glomerulosclerosis
Abstract
1. Introduction
2. Genetic Insights
2.1. Structure and Function of APOL1
2.2. APOL1 Variants (G1 and G2)
3. Pathogenic Mechanisms
3.1. Podocyte Injury
Mechanism | Description | Cellular Effects | References |
---|---|---|---|
Podocyte Dysfunction | Cytotoxic ion channel activity | Proteinuria; podocyte detachment | [26,32] |
Mitochondrial Dysfunction | Disruption of mitochondrial homeostasis | Energy deficits; oxidative stress | [35,36] |
ER Stress | Induction of unfolded protein response | Cellular apoptosis | [34,37] |
Lipid Dysregulation | Altered lipid metabolism in podocytes | Impaired membrane dynamics | [35] |
Inflammation | Activation of innate immune pathways (e.g., STING, JAK-STAT) | Chronic inflammatory signaling | [27,38,39] |
3.2. Non-Podocyte Injury
3.3. Cellular Pathways
3.3.1. Interferon Pathway
3.3.2. STING Pathway
3.3.3. JAK-STAT Pathway
4. Clinical Implications
4.1. ARIC Study
4.2. NEPTUNE Study
4.3. CKiD Study
4.4. CureGN Study
4.5. APOLLO Study
5. Treatment
5.1. Baricitinib
5.2. Sparsentan
5.3. Diacylglycerol O-Acyltransferase 2 Inhibitors
5.4. Small-Molecule Inhibitors
5.5. Antisense Oligonucleotides
5.6. CRISPR-Cas9 Technology
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
APOL1 | Apolipoprotein L1 |
CKD | Chronic Kidney Disease |
ESKD | End-Stage Kidney Disease |
FSGS | Focal Segmental Glomerulosclerosis |
HR | High Risk |
IFN | Interferon |
LR | Low Risk |
eGFR | Estimated Glomerular Filtration Rate |
SNP | Single-Nucleotide Polymorphism |
SRNS | Steroid-Resistant Nephrotic Syndrome |
FSGS-UC | FSGS of Undetermined Cause |
HDL | High-Density Lipoprotein |
SRA | Serum Resistance-Associated |
TCA | Tricarboxylic Acid |
OXPHOS | Oxidative Phosphorylation |
UPS | Ubiquitin-Proteasome System |
JAK-STAT | Janus Kinase-Signal Transducer and Activator of Transcription |
STING | Stimulator of Interferon Genes |
ASO | Antisense Oligonucleotide |
LBW | Low Birth Weight |
NEPTUNE | Nephrotic Syndrome Study Network |
CKiD | Chronic Kidney Disease in Children |
DUPLEX | Sparsentan FSGS Clinical Trial |
CRISPR | Clustered Regularly Interspaced Short Palindromic Repeats |
References
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Study Name | Population Characteristics | Key Findings | Implications | References |
---|---|---|---|---|
NEPTUNE cohort | African American children with nephropathy | APOL1 HR variants linked to faster eGFR decline | Highlights need for early intervention | [61] |
CKiD Cohort | Children with CKD, including APOL1 variant carriers | APOL1 HR associated with faster progression of CKD | Underscores importance of genetic risk stratification | [2] |
ARIC Study | Older adults, APOL1 genotype association with CKD outcomes | APOL1 HR linked to increased risk of ESKD and cardiovascular events | Emphasizes systemic impact of APOL1 variants | [60] |
DUPLEX Trial | Adults with biopsy-proven FSGS | Sparsentan reduced proteinuria significantly | Supports dual endothelin–angiotensin blockade | [62] |
Genetic Epidemiology Study | Global population; APOL1 variant frequencies | G1 and G2 alleles prevalent in African ancestry | Emphasizes health disparities in CKD | [12,15] |
Therapeutic Approach | Mechanism of Action | Advantages | Limitations | References |
---|---|---|---|---|
Small-Molecule Inhibitors | Inhibit APOL1-mediated ion channel activity | Oral administration; promising preclinical data | Limited long-term data; early clinical stage | [68,69,70] |
Antisense Oligonucleotides | Reduce APOL1 mRNA expression | High specificity; targeted therapy | Requires frequent administration; high cost | [71] |
Gene-Editing Technologies | Correct APOL1 genetic variants via CRISPR | Potential for permanent correction | Ethical concerns; early-stage research | [43,69] |
JAK-STAT Pathway Inhibitors | Modulate inflammatory signaling pathways | Addresses downstream effects of APOL1 | Non-specific action on immune signaling | [38,39,55] |
Lipid Metabolism Modulators | Restore lipid homeostasis disrupted by APOL1 | Broad metabolic benefits | Indirect action on APOL1 mechanisms | [35,72] |
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Delrue, C.; Speeckaert, M.M. From Gene to Clinic: The Role of APOL1 in Focal Segmental Glomerulosclerosis. Sclerosis 2025, 3, 6. https://doi.org/10.3390/sclerosis3010006
Delrue C, Speeckaert MM. From Gene to Clinic: The Role of APOL1 in Focal Segmental Glomerulosclerosis. Sclerosis. 2025; 3(1):6. https://doi.org/10.3390/sclerosis3010006
Chicago/Turabian StyleDelrue, Charlotte, and Marijn M. Speeckaert. 2025. "From Gene to Clinic: The Role of APOL1 in Focal Segmental Glomerulosclerosis" Sclerosis 3, no. 1: 6. https://doi.org/10.3390/sclerosis3010006
APA StyleDelrue, C., & Speeckaert, M. M. (2025). From Gene to Clinic: The Role of APOL1 in Focal Segmental Glomerulosclerosis. Sclerosis, 3(1), 6. https://doi.org/10.3390/sclerosis3010006