APOL1 promotes endothelial cell activation beyond the glomerulus

Area of Science:

• Nephrology
• Vascular Biology
• Genetics

Background:

• Apolipoprotein L1 (APOL1) high-risk genotypes are linked to chronic kidney disease (CKD) in individuals of West African ancestry.
• Endothelial cells (ECs) play a critical role in CKD pathogenesis.
• The specific mechanisms by which APOL1 influences ECs in CKD remain incompletely understood.

Purpose of the Study:

• To investigate whether APOL1 high-risk genotypes contribute to CKD through intrinsic activation and dysfunction of kidney ECs.
• To identify molecular pathways and cellular changes associated with APOL1 expression in renal ECs.

Main Methods:

• Single cell RNA sequencing (scRNA-seq) analysis of kidney tissue from the Kidney Precision Medicine Project.
• Transcriptomic analysis of public datasets from African Americans with CKD and APOL1-expressing transgenic mice.
• In vitro studies using human induced pluripotent stem cell-derived ECs and glomerular ECs with APOL1 expression.

Main Results:

• APOL1 expression was detected in ECs across various renal vascular compartments.
• An EC activation signature was identified, characterized by increased intercellular adhesion molecule 1 (ICAM-1) and enrichment in leukocyte migration pathways.
• APOL1 expression in vitro increased ICAM-1 and PECAM-1 expression, leading to enhanced monocyte attachment to ECs.

Conclusions:

• APOL1 appears to induce EC activation in multiple renal vascular beds.
• This EC activation, involving increased ICAM-1 and monocyte adhesion, may be a key mechanism contributing to CKD.
• The effects of APOL1 on ECs may extend beyond the glomerular vasculature, impacting overall kidney health.