Predicting Kidney Function Decline in People Who Are at High Risk for Kidney Disease
A new study has found that levels of the protein suPAR in the blood can help predict whether kidney function will deteriorate in people with high-risk genetic variants of the gene APOL1. Genetic variants of APOL1, which are found primarily in individuals of African ancestry, are arguably the most important discovery about the pathogenesis of chronic kidney disease over the past several decades, and among the only established genetic factors contributing to the well-appreciated health disparities in kidney diseases in Blacks compared to Whites. Individuals with one or two copies of either the G1 or G2 variants of the APOL1 gene are protected from a potentially deadly infectious disease (African sleeping sickness) compared to people with only the G0 variant. However, those with any combination of two G1 and/or G2 variants of the gene are at increased risk of developing kidney disease.
Previous research showed that high levels of a protein called suPAR in the blood is associated with decline in kidney function and progression to chronic kidney disease. Because many people with the high-risk G1 and G2 APOL1 variants do not develop kidney disease, researchers explored whether blood suPAR levels can help predict whether African Americans with these genetic variants will experience declining kidney function. The scientists analyzed data that had been collected from participants of two other studies, which together included almost 1,100 African-American participants. Kidney function was determined by evaluating estimated glomerular filtration rate, which is a commonly used measurement of how well the kidneys are filtering wastes and extra fluid from the blood. The scientists found that in people with high-risk APOL1 variants, kidney function was likely to decline more rapidly over time in those with elevated plasma suPAR levels than those with lower suPAR levels.
Using another series of tests, the researchers asked whether suPAR could physically associate with the APOL1 protein, which is encoded by the APOL1 gene, and found that the G0, G1, and G2 proteins all interacted directly and tightly with suPAR. They also examined whether APOL1 and suPAR could bind to αvβ3 integrin, a protein complex known to mediate the action of suPAR in kidney cells. When in an activated state, αvβ3 integrin formed strong protein complexes with suPAR and the high-risk G1 and G2 APOL1 complexes; by contrast, it formed very weak complexes with low-risk, G0 variant APOL1 proteins.
The scientists then examined the functional effects of these protein interactions by measuring the stimulation of β3 integrin, a component of the αvβ3 integrin protein complex, in cultures of a type of human kidney cells called podocytes. The G1 and G2 variants of APOL1 could activate β3 integrin, but only when suPAR was added to the culture; the APOL1 G0 variant could not activate β3 integrin under any condition. They then injected female mice with DNA encoding either human G0, G1, or G2 APOL1 variants and found that mice with G1 or G2 excreted high levels of protein in their urine, and their podocytes appeared to be physically injured—two indicators of kidney damage. The G0 variant had no effect on these mice. However, when the APOL1 G2 variant was produced in mice that were genetically engineered to lack suPAR, urine protein levels were the same as in normal mice.
Taken together, these findings reveal that high levels of suPAR may play an important role in the kidney function decline observed in some people with APOL1 G1 and G2 variants, and thus may serve as a useful predictor of kidney disease. The direct interactions observed between APOL1, suPAR, and αvβ3 integrin proteins help provide a mechanistic explanation of how kidney damage develops in those with high-risk APOL1 genetic variants, and thus may pave the way for new therapeutic strategies to prevent or treat kidney disease in these populations.