Kidney Week

Abstract: SA-PO705

Reversal of Established CKD by Weekly Subcutaneous Recombinant Human Mutated Angiopoietin-Like 4

Session Information

• Glomerular Diseases: Therapeutic Strategies
  October 26, 2024 | Location: Exhibit Hall, 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 Medical Center, Chicago, Illinois, United States

Jose Luis Sanchez Gloria, PhD

• Ortega Lozano, Ariadna Jazmin, Rush University Medical Center, Chicago, Illinois, United States

Ariadna Jazmin Ortega Lozano, PhD

• Das, Ranjan, Rush University Medical Center, Chicago, Illinois, United States

Ranjan Das, PhD

• Kharlyngdoh, Joubert Banjop, Rush University Medical Center, Chicago, Illinois, United States

Joubert Banjop Kharlyngdoh, PhD

• Del Nogal Avila, Maria, Rush University Medical Center, Chicago, Illinois, United States

Maria Del Nogal Avila, PhD

• Donoro Blazquez, Hector, Rush University Medical Center, Chicago, Illinois, United States

Hector Donoro Blazquez, MSc

• Molina-Jijon, Eduardo, Rush University Medical Center, Chicago, Illinois, United States

Eduardo Molina-Jijon, PhD

• Mace, Camille E., Rush University Medical Center, Chicago, Illinois, United States

Camille E. Mace, PhD

• Avila-Casado, Carmen, Toronto General Hospital, Toronto, Ontario, Canada

Carmen Avila-Casado, MD, PhD

• Clement, Lionel C., Rush University Medical Center, Chicago, Illinois, United States

Lionel C. Clement, PhD

• Chugh, Sumant S., Rush University Medical Center, Chicago, Illinois, United States

Sumant S. Chugh, MD, FASN

Group or Team Name

• Glomerular Disease Therapeutics Laboratory.

Background

We investigated the therapeutic potential of recombinant mutated human Angiopoietin-like 4 (ANGPTL4), previously shown to reduce proteinuria in diabetic and FSGS (Buffalo Mna) rats (Clement LC Nat. Med. 2014), in established chronic kidney disease (CKD). ANGPTL4 binds integrins β₁ and β₅ (podocyte α₃β₁, glomerular endothelial α_vβ₅, interstitial capillary endothelial α₁β₁), and has potent anti-apoptotic activity.

Methods

Included with results.

Results

As a proof of concept, transgenic expression of wild type rat Angptl4 from adipose tissue in Buffalo Mna rats (372-B. Mna) prevented doubling of serum creatinine (measured by LC-MS) between age 6 to 8 months (P<0.001), eliminated tubulo-interstitial fibrosis, and improved glomerular morphology compared to B. Mna rats (n = 4 to 6 rats / group). Interstitial infiltrate in 372-B. Mna rats contained mostly macrophages. Recombinant human mutated ANGPTL4 protein 8520 (Nat. Med. 2014) was purified and ultra-purified from HEK 293 stable cell lines grown in FiberCell systems. In a declining dose study (starting with 500 μg weekly subcutaneous 8520 or control rat albumin, n = 5 ZSF1 diabetic rats / group), serum creatinine was lower in the 8520 group compared to control between week 5 (dose 500 μg; P<0.001) and week 9 (dose 125 μg; P<0.05), but not at subsequent lower doses. Within the 8520 group, serum creatinine was lower on week 9 than Day 0 (P<0.05). Upon euthanasia (week 28), interstitial capillary endothelium apoptosis (TUNEL stain) was lower in 8520 compared to control (P<0.001). Using the lowest effective 8520 dose (125 μg / week) with or without ACE inhibitor (enalapril 5 mg/Kg/day), inulin clearance GFR at 16 weeks was higher in 8520 (P<0.05) and 8520 + enalapril (P<0.01) groups, tubulo-interstitial fibrosis lower (P<0.01 both groups) and interstitial capillary endothelial apoptosis lower (P<0.001 both groups) compared to control treated ZSF1 rats (age on Day 0, 19 weeks; n = 4-5 rats / group). Enalapril alone did not improve GFR. Studies with higher doses of 8520 are in progress.

Conclusion

8520 reverses established CKD to improve GFR via a multi-compartment anti-apoptosis effect that keeps capillaries open for repair.

Funding

• NIDDK Support