DOI: 10.34067/kid.0000001253 ISSN: 2641-7650
Impact of APOL1-Associated Pregnancy Complications on Kidney Disease Phenotypes in a HIV-Associated Nephropathy Mouse Model
Zhenzhen Wu, Timur Azhibekov, Chunfa Huang, Jane K. Nguyen, Korey R. Bartolomeo, Oliver Wessely, John F. O'Toole, John R. Sedor, Leslie A. Bruggeman
Background
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. Since all these transgenic models are hemizygous, crosses produced offspring of four genotypes: wildtype 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 wildtype 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 wildtype 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
Co-expression 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, suggesting a second mechanism by which
APOL1
risk variant expression may impact long-term kidney function.