Abstract: TH-PO460
Anti-Inflammatory Therapy in CKD Using Drug-Delivery Technology: Mechanisms and Effects of Renal NFkB Inhibition
Session Information
- CKD: Clinical, Outcomes, Trials - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1601 Pathology and Lab Medicine: Basic
Authors
- Chade, Alejandro R., University of Mississippi, Jackson, Mississippi, United States
- Engel, Jason E., University of Mississippi Medical Center, Jackson, Mississippi, United States
- Williams, Erika, University of Mississippi Medical Center, Jackson, Mississippi, United States
- Williams, Maxx, University of Mississippi, Jackson, Mississippi, United States
- Howell, John A., University of Mississippi Medical Center, Jackson, Mississippi, United States
- Bidwell, Gene L., University of Mississippi Medical Center, Jackson, Mississippi, United States
Background
The NFkB pathway mediates chronic inflammation in chronic kidney disease (CKD). The NFkB p50/p65 heterodimer, once activated, translocates into the cell nucleus to stimulate inflammation via defining macrophage phenotype and production of inflammatory cytokines. We designed a construct of an inhibitor of the NFkB-p50 subunit (p50i) fused to a drug carrier (elastin-like polypeptide, ELP) equipped with a cell-penetrating peptide. We hypothesize that ELP-p50i therapy will inhibit production of inflammatory cytokines, ameliorate renal inflammation and injury in CKD
Methods
We first exposed LPS-stimulated macrophages to ELP-p50i to confirm its NFkB inhibitory activity. Next, CKD was induced in 10 pigs (bilateral renal artery stenosis+dyslipidemia). After 6 weeks of CKD, pigs were treated with single intra-renal ELP-p50i therapy (10 mg/kg) or placebo (n=5 each). Glomerular filtration (GFR) was quantified using multi-detector CT before and 8 weeks after treatment. Pigs were then euthanized and renal expression of NFkB, downstream mediators of NFkB signaling, circulating inflammatory cytokines, and renal morphology were quantified
Results
ELP-p50i inhibits nuclear translocation of NFkB in vitro. Fourteen weeks of CKD increased renal NFkB nuclear expression and renal mRNA expression of downstream mediators (TNF-α, MCP-1, and IL-6), accompanied by blunted GFR, increased plasma creatinine, and renal fibrosis. All these changes were improved after ELP-p50i therapy. Notably, intra-renal therapy also reduced circulating TNF-α and MCP-1 in CKD (Figure)
Conclusion
Our study provides mechanistic support, in vitro and in vivo, to the therapeutic potential of a targeted anti-inflammatory strategy using a novel drug-delivery technology. It also suggests that the kidney in CKD is both a source and target of inflammation that could be offset via specific molecular inhibition of NFkB signaling
Funding
- Other NIH Support