Abstract: TH-PO0358
Reversal of Diabetic Nephropathy and FSGS by GFR Criteria Using Recombinant Mutated Human Angiopoietin-Like 4 (Protein 8520), a First-in-Class Biological Drug Candidate, to Induce Repair
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Sanchez Gloria, Jose Luis, Rush University, Chicago, Illinois, United States
- Ortega Lozano, Ariadna Jazmin, Rush University, Chicago, Illinois, United States
- Kharlyngdoh, Joubert Banjop, Rush University, Chicago, Illinois, United States
- Das, Ranjan, Rush University, Chicago, Illinois, United States
- Del Nogal Avila, Maria, Rush University, Chicago, Illinois, United States
- Donoro Blazquez, Hector, Rush University, Chicago, Illinois, United States
- Mace, Camille E., Rush University, Chicago, Illinois, United States
- Molina-Jijon, Eduardo, Rush University, Chicago, Illinois, United States
- Avila-Casado, Carmen, University Health Network, Toronto, Ontario, Canada
- Clement, Lionel C., Rush University, Chicago, Illinois, United States
- Chugh, Sumant S., Rush University, Chicago, Illinois, United States
Group or Team Name
- Glomerular Disease Therapeutics Laboratory
Background
We administered weekly subcutaneous recombinant protein 8520, previously shown to reduce proteinuria (Clement LC Nat. Med. 2014), to FSGS (Buffalo Mna) and diabetic nephropathy (ZSF1) rats with established CKD.
Methods
GFR was assessed by LC-MS serum creatinine or inulin clearance, morphometric analysis and TUNEL staining conducted, and infiltrating cells stained for CD45 (all leucocytes), CD68 (macrophages), CD86 (M1 macrophages) and CD206 (M2 macrophages).
Results
As a proof of concept, transgenic expression of wild type rat Angptl4 from adipose tissue in Buffalo Mna rats (372-B. Mna) resulted in unchanged serum creatinine between age 3 (0.20+0.02) and 8.5 (0.20+0.001) months, whereas B. Mna rat serum creatinine more than doubled between age 6 (0.22+0.03) and 8.5 (0.49+0.04) months (P<0.05). In 372-B. Mna rats, tubulo-interstitial fibrosis was eliminated, glomerular morphology improved, and interstitial infiltrate had predominant M2 macrophages. Using weekly subcutaneous 8520, enalapril, 8520 + enalapril or control in ZSF1 diabetic rats (age on Day 0, 19 weeks; n=4-5 rats/group), inulin clearance GFR at 16 weeks was higher in 8520 (3.96+0.22 ml, P<0.05 Vs control 3.3+0.17 ml) and 8520 + enalapril (4.12+0.12 ml P<0.01 Vs control), tubulo-interstitial fibrosis lower (P<0.01 both 8520 groups Vs control) and interstitial capillary endothelial apoptosis (TUNEL) lower (P<0.001 both 8520 groups Vs control or enalapril). Enalapril alone did not improve GFR (3.79+0.14 ml, P>0.05 vs control). In B. Mna rats (age 7 months, n=8 rats/group) treated with control, 8520, enalapril, or 8520 + enalapril for 17 weeks, serum creatinine in 8520 + enalapril declined from baseline (0.40+0.03) starting 6 weeks (0.28+0.02, P <0.05 Vs baseline) to a nadir at 8 weeks (0.27+0.01, P<0.01 Vs baseline), remained nearly flat in 8520 alone, doubled in enalapril group (0.81+0.18, P <0.01 Vs baseline) and tripled in the control group (1.43+0.43, P <0.01 Vs baseline). Morphology was significantly better in both 8520 groups.
Conclusion
In summary, this is the first ever demonstration of true CKD reversal in established FSGS and diabetic nephropathy mediated by 8520 induced repair.
Acknowledgment
NIH grants R01DK137919, R01DK145476, R01DK101637
Funding
- NIDDK Support