Abstract: FR-PO706

Recombinant Mutated Human Angiopoietin-Like 4 Reduces the Progression of CKD Due to Diabetes and FSGS

Session Information

Category: Glomerular

  • 1002 Glomerular: Basic/Experimental Pathology

Authors

  • Del Nogal Avila, Maria, Rush University Medical Center, Chicago, Illinois, United States
  • Chugh, Sumant S., Rush University Medical Center, Chicago, Illinois, United States
  • Donoro blazquez, Hector, Rush University Medical Center, Chicago, Illinois, United States
  • Kharlyngdoh, Joubert Banjop, Rush University Medical Center, Chicago, Illinois, United States
  • Das, Ranjan, Rush University Medical Center, Chicago, Illinois, United States
  • Molina-Jijon, Eduardo, Rush University Medical Center, Chicago, Illinois, United States
  • Filip, Szymon, Rush University Medical Center, Chicago, Illinois, United States
  • Avila-Casado, Carmen, University Health Network, University of Toronto, Toronto, Ontario, Canada
  • Mace, Camille E., Rush University Medical Center, Chicago, Illinois, United States
  • Clement, Lionel C., Rush University Medical Center, Chicago, Illinois, United States
Background

Angptl4 is a major molecular mediator of nephrotic syndrome secreted in two forms: a hyposialylated form secreted from podocytes that causes proteinuria in minimal change disease (MCD), and a sialylated circulating form secreted from skeletal muscle, heart and adipose tissue that reduces proteinuria and causes hypertriglyceridemia in nephrotic syndrome. Short-term studies with FSGS and diabetic nephropathy (DN) rats using recombinant mutant Angptl4 reduces proteinuria without causing hypertriglyceridemia.

Methods

We injected recombinant human mutated Angptl4 (protein 8520) or control albumin weekly subcutaneously into rats with FSGS (B. Mna; n=6/group) and DN (ZSF1; n=5/group) according to different dosing regimens. Recombinant sialylated Angptl4 mutant 8520 was produced in HEK923 cells growing in hollow fiber bioreactors.
To study the effect of higher native circulating sialylated Angptl4 expression in FSGS, adipose tissue-specific Angptl4 TG (372) were backcrossed for 8 generations into B. Mna rats.

Results

ZSF1 rats treated with 500µg of 8520 had less proteinuria (38.95±6.6 mg per 18h) than controls (64.8±3.3 mg per 18h) after 3 weeks of weekly treatment (p<0.05). When the dose was reduced, proteinuria was not significantly different between the two groups. Differences were restored after increasing the amount of protein at week 13 (8520: 172.4±14.5 mg per 18h and control 210.6±13.5 mg per 18 h; p<0.05). BUN and creatinine levels were significantly lower in rats treated with 8520 at different time-points, with better histology morphology than controls after 28 weeks of treatment.
After 15 weeks of Angptl4 mutant therapy, B. Mna rats had less prominent visceral epithelial cells, less VEP hypertrophy, less tubular-interstitial inflammation and less periglomerular fibrosis compare with control group.
8 month old male 372-B. Mna has less creatinine and BUN than non-TG B. Mna rats and remarkable improved histology. Female 372-B. Mna showed less proteinuria (238.5±39.4 mg per 18h) than non-TG B. Mna rats (307.8±15.7 mg per 18h) (p=0.048).

Conclusion

These findings suggest a protective effect of recombinant mutated human Angptl4, as well as increased circulating native rat Angptl4 in the progression of CKD.

Funding

  • NIDDK Support