Abstract: TH-OR110

Therapeutic Angiogenesis in CKD

Session Information

  • Scarred for Life?
    November 02, 2017 | Location: Room 394, Morial Convention Center
    Abstract Time: 04:54 PM - 05:06 PM

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Chade, Alejandro R., University of Mississippi, Jackson, Mississippi, United States
  • Bidwell, Gene L., University of Mississippi, Jackson, Mississippi, United States
Background

Renal microvascular (MV) loss in CKD correlates with progressive loss of renal function. However, whether this is an association or a cause-effect relation is unclear. We developed a drug-delivery construct of an elastin-like polypeptide (ELP) fused to VEGF-A and showed that intra-renal infusion of ELP-VEGF in CKD improved renal function. We tested the hypothesis that ELP-VEGF therapy may induce long-term recovery in CKD by stimulation of MV proliferation and repair.

Methods

CKD was induced in 8 pigs by bilateral renal artery stenosis and diet-induced dyslipidemia. Blood pressure was continuously measured (telemetry). Bilateral RBF and GFR were quantified in vivo using multi-detector CT after 6 weeks of CKD, and then pigs randomly treated with a single intra-renal administration of ELP-VEGF (100 μg/kg) or placebo (n=4 each). In vivo studies were repeated 4 and 8 weeks after treatment, pigs were then euthanized, and ex vivo studies performed to quantify renal MV density (micro-CT), MV remodeling, and angiogenic signaling

Results

RBF and GFR were reduced in CKD, accompanied by hypertension, cortical and medullary MV remodeling and loss, and blunted expression of VEGF, HGF, specific VEGF/HGF receptors, and markers of cell progenitors (Oct-4 and CD-34). However, CKD+ELP-VEGF pigs showed 28% and 53% improvement in RBF and GFR 4 weeks after treatment, and 46% and 74% recovery after 8 weeks, respectively (compared to pre-treatment), followed by increased expression of angiogenic and progenitor cell markers, reduced MV loss and remodeling [Figure]

Conclusion

Therapeutic angiogenesis via single-dose ELP-VEGF therapy stimulates renal neovascularization and MV repair, which likely drove recovery of renal function and improved CKD stage from 2 to 1. CKD recovery was progressive, and our data imply that underlying mechanisms of the long-term effects may involve sustained stimulation of cell progenitors to and within the kidney.

Funding

  • Other NIH Support