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Abstract: FR-PO152

Weekly Subcutaneous Mutated Human Angiopoietin – Like 4 (8520) Improves CKD in Diabetic Rats via an Anti-Endothelial Apoptosis Mechanism

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

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

Group or Team Name

  • Glomerular Disease Therapeutics Laboratory
Background

We previously showed that single intravenous dosing of recombinant mutated human Angptl4 (8520) reduces proteinuria for over 2 weeks in diabetic rats (Clement L, Mace C, et al Nature Medicine Jan 2014). We now tested whether subcutaneous doses in diabetic rats would reduce CKD.

Methods

We treated male ZSF1 rats (n = 5 rats / group) with 8520 or rat albumin once a week subcutaneously in declining doses, starting with 500 μg per dose on Week 0 (W0) to 125 μg on Week 9, to 100 μg on Week 15 and 50 μg on Week 16, after which the treatment was stopped and rats sacrificed on W20. Food and water intake, proteinuria, blood glucose, plasma human Angptl4 levels and serum parameters were measured periodically.

Results

Pharmacokinetic assessment of plasma human Angptl4 (8520) levels showed elevated levels between W1 and W15 at dose ranges between 500 μg and 100 μg subcutaneously per week. Plasma levels were statistically similar at doses between 500 μg and 125 μg. Plasma creatinine was significantly lower in the treatment group (P < 0.01 to P < 0.001) between doses 500 and 125 μg, and BUN between 500 and 100 μg (P < 0.05). 18-hour proteinuria was mostly similar between treatment and control groups, and as were the plasma glucose and triglyceride levels. Histological improvement revealed very significant improvement morphometric parameters in the treatment compared to control group. TUNEL staining for apoptosis revealed very significant reduction in interstitial capillary endothelial apoptosis in the treatment Vs. the control group (P < 0.001).

Conclusion

Weekly subcutaneous doses of mutated human Angptl4 in ZSF1 rats improves GFR at doses between 500 and 125 μg. Despite sub-therapeutic doses and stopping treatment towards the end, morphology was significantly improved, suggesting a memory effect. The absence of effects on proteinuria and the highly significant difference in interstitial capillary endothelial apoptosis suggests that the beneficial effects of subcutaneous dosing are mediated by preserving interstitial capillaries and presumably promoting repair in the treatment group.

Funding

  • NIDDK Support