Researchers report that soluble urokinase plasminogen activator receptor (suPAR) synergizes with the apolipoprotein L1 (APOL1) risk variants G1 and G2 to activate αvβ3 integrin on podocytes. “Our findings provide an epidemiological and mechanistic explanation for renal disease in APOL1 risk carriers,” says lead researcher Jochen Reiser.

In two separate cohorts of African Americans (comprising >1,000 individuals), Reiser and colleagues show that suPAR levels modify the association between APOL1 genotype and annual decline in estimated glomerular filtration rate. “APOL1 high-risk carriers had an attenuated decline in kidney function with lower levels, and increased decline with higher levels of plasma suPAR,” explains Reiser.

suPAR is ... a modifiable target to combat renal disease in carriers of APOL1 risk alleles

Using surface plasmon resonance assays, the researchers identified high-affinity interactions between suPAR, APOL1 and αvβ3 integrin. All three APOL1 variant proteins bound suPAR with very high affinity; however, the risk variants APOL1 G1 and G2 bound suPAR-activated αvβ3 integrin with substantially higher affinity than did the reference variant APOL1 G0.

In human podocyte cultures, addition of suPAR plus APOL1 G1 or G2, but not of suPAR plus APOL1 G0, resulted in substantial activation of β3 integrin and cell detachment, suggesting toxic effects on podocytes. Similarly in wild-type mice, but not in mice deficient in Plaur, which encodes uPAR and suPAR, expression of human APOL1 G1 or G2, but not of APOL1 G0, resulted in β3 integrin activation, podocyte foot-process effacement and substantial proteinuria.

The researchers conclude that synergy of circulating suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism of chronic kidney disease. “SuPAR activates αvβ3 integrin to enable binding of APOL1, but only binding of the risk variants produces pathological integrin activation beyond that which is achieved by suPAR alone,” says Reiser. “SuPAR is therefore a modifiable target to combat renal disease in carriers of APOL1 risk alleles.”