Hypertension Does Not Enhance Proteinuria in African Green Monkeys that Exhibit One or More Copies of an APOL1‐Like Gene Insertion
Authors: Barrett Lucas D.G. , Weaver Chelsea C. , Rhoads Megan K. , Osborn Jeffrey L. 
Published: April 2020

Historically, people of African descent have increased instances of early onset kidney disease which can be correlated with genetic variants at the Apolipoprotein L‐1 (APOL1) gene locus. APOL1 is a component of high density lipoprotein (HDL) that serves as a serum trypanolytic factor to protect against T. brucei, which causes African sleeping sickness. Genetic variants in APOL1 elicit some resistance to T. brucei, and have been linked to increased risk of early‐onset end‐stage renal disease (ESRD). A translational animal model is key to understanding the pathogenesis of APOL1‐mediated ESRD. The African Green Monkey (AGM) develops spontaneous hypertension with renal glomerular pathologies. AGMs exhibit a genetic insert at the APOL1 locus homologous to that in the human genome that is associated with HTN in homozygous AGMs. APOL1‐mediated ESRD typically develops in response to a second hit stressor such as HTN. We hypothesized that hypertensive (HT) AGMs with at least one copy of the APOL1‐like insertion (I) will have altered kidney function compared to HT AGMs without the insertion (NI). Systolic (SBP) and diastolic (DBP) blood pressures and heart rates were measured with forearm plethysmography. AGMs with SBP ≤ 120 were normotensive (NT) and SBP ≥ 140 were HT. Daily urine output and water intake was collected from single‐housed AGMs for three consecutive days. During urine collections, all animals were fed a standard, nonhuman primate chow with ad libitum water. Urinary protein and plasma creatinine were measured using standard colorimetric techniques. SBP was not different between HT NI AGMs (163 ± 3.8 mm Hg, n = 12) and HT I AGMs (158 ± 7.3mm Hg, n = 7, p > 0.05) nor was SBP different between NT NI AGMs (94.3 ± 4.0 mm Hg, n = 17) and NT I AGMs (103 ± 6.3 mm Hg, n = 6, p > 0.05). Body weight was used to approximate age and was not different between NI and I AGMs (p > 0.05). Protein excretion was higher for HT NI AGMs (416.3 ± 44.8 mg/day, n = 10) than for HT I AGMS (289.2 ± 33.0 mg/day, n = 6, p < 0.05) and higher for NT NI AGMs (450.7 ± 43.3 mg/day, n = 15) than for NT I AGMs (227.0 ± 83.6 mg/day, n = 4, p < 0.05). Plasma creatinine concentration was not different between NT NI and NT I AGMs (p > 0.05) as well as HT NI and HT I AGMs (p > 0.05). Plasma creatinine concentration and protein excretion rates were not different between HT and NT NI AGMs (p > 0.05) nor were they different between HT and NT I AGMs (p > 0.05). Thus, at this age, differences in plasma creatinine concentration and protein excretion were likely due to insertion status and not BP phenotype. These results indicate that in the AGM a single copy of the APOL1‐like insertion may not be sufficient to cause progression to ESRD. In humans, the high‐risk genotypes for APOL1‐mediated ESRD have two copies of the variant, therefore future studies should aim to assess more homozygous animals. The AGM as a model organism will allow investigation of links between HTN and APOL1‐like genetic variants that could result in novel treatments and targets for patients with APOL1‐mediated renal dysfunction.Support or Funding InformationUndergraduate Summer Research Fellowship, American Physiological Society; Summer Research and Creativity Fellowship, University of Kentucky Office of Undergraduate Research