Novel Human Podocyte Cell Model Carrying G2/G2 APOL1 High-Risk Genotype

Area of Science:

• Nephrology
• Genetics
• Cell Biology

Background:

• Apolipoprotein L1 (APOL1) high-risk genotypes (HRG) are associated with non-diabetic kidney diseases in African populations.
• The exact mechanisms of APOL1 risk variants causing kidney cell injury are not fully understood.
• Current research often relies on animal or gene-edited cell models.

Purpose of the Study:

• To develop and characterize a human podocyte cell line from a donor with APOL1 HRG G2/G2.
• To investigate the functional consequences of APOL1 expression in human podocytes.
• To establish a valuable model for studying APOL1-mediated podocyte injury.

Main Methods:

• Developed conditionally immortalized human podocyte cell lines from urine of an APOL1 G2/G2 donor.
• Induced APOL1 expression using polyinosinic-polycytidylic acid (poly(I:C)).
• Utilized a previously established APOL1 wild-type (G0/G0) podocyte cell line as a control.

Main Results:

• Both G2/G2 and G0/G0 podocytes upregulated APOL1 expression upon poly(I:C) exposure, leading to detachment, reduced viability, and increased apoptosis.
• G2/G2 podocytes exhibited distinct alterations: CD2AP upregulation, cytoskeleton changes, reduced autophagic flux, and increased permeability under perfusion.
• These genotype-independent and dependent effects highlight specific cellular dysfunctions associated with APOL1 HRG.

Conclusions:

• The developed human APOL1 G2/G2 podocyte cell line is a robust tool for studying APOL1-induced kidney injury.
• This model facilitates the elucidation of mechanisms underlying podocyte dysfunction in APOL1-associated nephropathies.
• It aids in understanding the cellular functions of APOL1 and its role in kidney disease pathogenesis.