Molecular Targeting of Renal Inflammation using Drug Delivery Technology to Inhibit NF-kB Improves Renal Recovery in Chronic Kidney Disease.

Inflammation is a major determinant for the progression of chronic kidney disease (CKD). Nuclear-factor-kappa-B (NF-kB) is a master transcription factor up-regulated in CKD that promotes inflammation, regulates apoptosis, and vascular remodeling. We aimed to modulate this pathway for CKD therapy in a swine model of CKD using a peptide inhibitor of the NF-kB p50 subunit (p50i) fused to a protein carrier (elastin-like polypeptide, ELP) and equipped with a cell-penetrating peptide (SynB1). We hypothesize that intra-renal SynB1-ELP-p50i therapy will inhibit NF-kB-driven inflammation and induce renal recovery. CKD was induced in 14 pigs. After 6 weeks, pigs received single intra-renal SynB1-ELP-p50i therapy (10 mg/kg) or placebo (n=7 each). Renal hemodynamics were quantified in vivo using multi-detector CT before and 8 weeks after treatment. Pigs were then euthanized. Ex vivo studies were performed to quantify renal activation of NF-kB, expression of downstream mediators of NF-kB signaling, renal microvascular density, inflammation, and fibrosis. Fourteen weeks of CKD stimulated NF-kB signaling and downstream mediators (e.g. TNF-α, MCP-1, and-6) accompanying loss of renal function, inflammation, fibrosis, and microvascular rarefaction vs. controls. All these were improved after SynB1-ELP-p50i therapy, accompanied by reduced circulating inflammatory cytokines as well, which were evident up to 8 weeks after treatment. Current treatments for CKD are largely ineffective. Our study shows the feasibility of a new treatment to induce renal recovery by offsetting inflammation at a molecular level. It also supports the therapeutic potential of targeted inhibition of the NF-kB pathway using novel drug-delivery technology in a translational model of CKD.