Impact of Apolipoprotein L1-Associated Pregnancy Complications on Kidney Disease Phenotypes in a HIV-Associated Nephropathy Mouse Model.

KEY POINTS: G0 coexpression did not improve CKD outcomes in a mouse model of HIV-associated nephropathy. Apolipoprotein L1 is expressed in the placenta, and risk variants are associated with preeclampsia, low birth weight, and reduced podocyte and glomerular density. Apolipoprotein L1 kidney disease risk may be mediated by apolipoprotein L1-associated birth complications negatively affecting kidney development.

BACKGROUND

Apolipoprotein L1 (APOL1) polymorphisms are a significant risk factor of kidney disease including HIV-associated nephropathy (HIVAN), but a comprehensive understanding of the pathogenic mechanism remains unclear.

METHODS

APOL1 transgenic models expressing APOL1 -G0 and the kidney disease risk-associated APOL1 -G1 variant were intercrossed with the Tg26 mouse model of HIVAN. Because all these transgenic models are hemizygous, crosses produced offspring of four genotypes: wild-type (WT) mice, APOL1 , Tg26, and dual transgenic mice expressing both APOL1 and Tg26 transgenes. Kidney function, pathology, and transgene expression patterns were examined in addition to podocyte and glomerular densities.

RESULTS

The WT and APOL1 G0 or G1 mice did not develop kidney disease, whereas Tg26 and dual transgenic mice developed severe kidney disease consistent with the Tg26 HIVAN phenotype. The outcome of the G1/Tg26 intercross was expressed during pregnancy with neonatal complications that included a preeclampsia-like phenotype, low fetal/placental weight ratios, low birth weights, and fewer dual transgenic offspring that survived to adulthood. Some adult offspring from the G1/Tg26 intercross also had reduced podocyte densities and fewer glomeruli. This included the WT and APOL1 -G1 mice, suggesting a systemic effect of the preeclampsia phenotype on the entire litter. The G0/Tg26 intercross also demonstrated kidney pathology and albuminuria similar to the G1/Tg26 intercross.

CONCLUSIONS

Coexpression of G0 in the Tg26 mouse model was not protective against kidney disease. In addition, the G1-associated pregnancy complications, reduced podocyte and glomerular densities, suggest a second mechanism by which APOL1 risk variant expression may affect long-term kidney function.