Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 2, 2025

Chronic kidney disease affects ~10% of people worldwide and there are no modifying therapeutics that address the underlying cause any form disease. Genome wide association studies have identified G1 G2 variants in apolipoprotein L1 (APOL1) gene as major contributors to a subtype proteinuric now referred APOL1-mediated (AMKD). We hypothesized inhibition APOL1 could therapeutic potential for this genetically-defined Here we describe development preclinical assays discovery potent specific inhibitors with drug-like properties. provide evidence channel activity drives podocyte injury stops cell death damage transgenic mouse model. These data, combined clinical data from our previously published phase 2 proof-of-concept study, support treatment AMKD. Apolipoprotein genetic contribute authors report characterization selective ion

Language: Английский

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Advances in kidney disease: pathogenesis and therapeutic targets

Frontiers in Medicine, Journal Year: 2025, Volume and Issue: 12

Published: Feb. 14, 2025

Chronic kidney disease (CKD) is a global public health issue characterized by progressive loss of function, which end-stage (ESKD) the last stage. The increase in prevalence CKD linked to increasing traditional risk factors, including obesity, hypertension, and diabetes mellitus, as well metabolic particularly insulin resistance, dyslipidemia, hyperuricemia. Mortality comorbidities, such cardiovascular complications, rise steadily function deteriorates. Patients who progress ESKD require long-term replacement therapy, transplantation or hemodialysis/peritoneal dialysis. It currently understood that crucial aspect involves persistent, low-grade inflammation. In addition, increased oxidative stress, endothelial dysfunction, vascular calcification from poor calcium phosphate metabolism, difficulties with coagulation are some complex molecular pathways underlying CKD-related ESKD-related issues. Novel mechanisms, microbiome dysbiosis apolipoprotein L1 gene mutation, have improved our understanding mechanisms. High Africa has been APOL1 high-risk alleles. 3-fold African Americans compared European mainly attributed variants chromosome 22q12 locus. Additionally, role new therapies SGLT2 inhibitors, mineralocorticoid receptor antagonists, channel inhibitors offers therapeutic targets slowing down progression chronic disease. This review describes recent mechanisms emerging targets.

Language: Английский

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The Janus-faced functions of Apolipoproteins L in membrane dynamics

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: March 13, 2024

Abstract The functions of human Apolipoproteins L (APOLs) are poorly understood, but involve diverse activities like lysis bloodstream trypanosomes and intracellular bacteria, modulation viral infection induction apoptosis, autophagy, chronic kidney disease. Based on recent work, I propose that the basic function APOLs is control membrane dynamics, at least in Golgi mitochondrion. Together with neuronal calcium sensor-1 (NCS1) calneuron-1 (CALN1), APOL3 controls activity phosphatidylinositol-4-kinase-IIIB (PI4KB), involved both mitochondrion fission. Whereas secreted APOL1 induces African trypanosome through permeabilization parasite mitochondrion, conditions non-muscular myosin-2A (NM2A)-mediated transfer PI4KB from to under interfering PI4KB-APOL3 interaction, such as C-terminal variant expression or virus-induced inflammatory signalling. mitophagy complementary interactions fission factor fusion vesicle-associated protein-8 (VAMP8). In mice, could be exerted by mAPOL9 mAPOL8, respectively. Perspectives regarding mechanism treatment APOL1-related disease discussed, well speculations additional functions, APOL6 involvement adipocyte dynamics interaction myosin-10 (MYH10).

Language: Английский

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Integration of metabolomic and transcriptomic analyses reveals regulatory functions of the ChREBP transcription factor in energy metabolism

Cell Reports, Journal Year: 2025, Volume and Issue: 44(2), P. 115278 - 115278

Published: Feb. 1, 2025

The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in to feeding. Integrated transcriptomic metabolomic analyses rats with GalNac-siRNA-mediated suppression ChREBP expression liver reveal other functions. GalNac-siChREBP treatment reduces involved coenzyme A (CoA) biosynthesis, lowering CoA short-chain acyl-CoA levels. Despite pyruvate kinase, levels are maintained, possibly via increased amino acid transporters. In addition, multiple anaplerotic enzymes is decreased by treatment, affecting TCA cycle intermediates. Finally, GalNAc-siChREBP suppresses late steps purine NAD synthesis, increases precursors end products both pathways. sum, our study reveals functions beyond its canonical roles include regulation substrate transport, mitochondrial function, energy balance.

Language: Английский

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APOL1-associated kidney disease: modulators of the genotype-phenotype relationship

Current Opinion in Nephrology & Hypertension, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Apolipoprotein-L1 (APOL1) G1 and G2 risk variants, found in people of recent west sub-Saharan African ancestry, dramatically increase the likelihood kidney disease, yet incomplete penetrance an diverse clinical manifestations underscore need to understand molecular environmental factors that modulate APOL1-mediated toxicity. Recent studies confirm variants exert a toxic gain-of-function effect, exacerbated by inflammatory triggers such as HIV infection COVID-19. Epigenetic mechanisms microRNA pathways further APOL1 expression, influencing disease penetrance. Multiple models have clarified how subcellular localization, signal peptide processing, interactions with endoplasmic reticulum may contribute pathogenesis. Therapeutic advances include inhibitors targeting ion channel activity strategies block key signaling pathways. These findings highlight multifaceted process driven both intrinsic potential numerous extrinsic triggers. Understanding this complex interplay will be pivotal for stratification development precision therapies, potentially improving outcomes populations disproportionately affected APOL1-associated disease.

Language: Английский

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Kidney disease in patients with HIV

Current Opinion in HIV and AIDS, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Purpose of review With the advent antiretroviral therapy, people with HIV (PWH) are living longer and at risk developing age-related comorbid illnesses, such as chronic kidney disease (CKD). The purpose this article is to summarize recent advances in diagnosis management PWH, ultimately inform clinical practice. Recent findings Individuals West African descent often genetically predisposed develop CKD. Among carriers APOL-1 variant, Na + /K transport has been identified proximal driver APOL-1-mediated pathogenesis. use urine biomarkers CKD among PWH supported comparable general population. Additionally, novel therapies, sodium-glucose cotransporter-2 inhibitors glucagon-like peptide 1 receptor agonists can potentially offer significant benefit Summary Despite being an underrepresented group trials, research have broadened our understanding PWH. Given that experience increased CKD, early detection vital improving quality life overall healthcare outcomes.

Language: Английский

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The mislaid clue to APOL1 kidney disease prevention in blacks

Journal of Human Hypertension, Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Language: Английский

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APOL1 nephropathy – a population genetics success story

Current Opinion in Nephrology & Hypertension, Journal Year: 2024, Volume and Issue: 33(4), P. 447 - 455

Published: Feb. 28, 2024

More than a decade ago, apolipoprotein L1 ( APOL1 ) risk alleles designated G1 and G2, were discovered to be causally associated with markedly increased for progressive kidney disease in individuals of recent African ancestry. Gratifying progress has been made during the intervening years, extending development clinical testing genomically precise small molecule therapy accompanied by emergence RNA medicine platforms within just over decade.

Language: Английский

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APOL1-Mediated Kidney Disease

JAMA, Journal Year: 2024, Volume and Issue: 331(19), P. 1668 - 1668

Published: April 25, 2024

This JAMA Insights reviews the origin of APOL1 high-risk genetic variants, defines APOL1-mediated kidney disease, and discusses recommendations for screening management.

Language: Английский

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The Two Levels of Podocyte Dysfunctions Induced by Apolipoprotein L1 Risk Variants

Kidney and Dialysis, Journal Year: 2024, Volume and Issue: 4(2), P. 126 - 143

Published: June 7, 2024

Apolipoprotein L1 (APOL1) nephropathy results from several podocyte dysfunctions involving morphological and motility changes, mitochondrial perturbations, inflammatory stress, alterations in cation channel activity. I propose that this phenotype increased hydrophobicity of the APOL1 risk variants, which induces two distinct types dysfunctions. On one hand, hydrophobic interactions with APOL3 cause intracellular variant isoforms to impair both control Golgi PI(4)P kinase-B (PI4KB) activity membrane fusion, triggering actomyosin reorganisation together mitophagy apoptosis inhibition (hit 1). other plasma may extracellular activate toxic Ca2+ influx K+ efflux by TRPC6 BK channels, respectively 2), presumably due APOL1-mediated cholesterol clustering microdomains. hit 2 depends on low HDL-C/high ratio, such as occurs cell culture vitro, or during type I-interferon (IFN-I)-mediated inflammation.

Language: Английский

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