Impact of PAMAM delivery systems on signal transduction pathways in vivo: Modulation of ERK1/2 and p38 MAP kinase signaling in the normal and diabetic kidney

Abstract

The in vivo impact of two generation 6 cationic polyamidoamine (PAMAM) dendrimers on cellular signaling via extracellular-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK), as well as their relationship to epidermal growth factor receptor (EGFR), were studied in the normal and/or diabetic rat kidney. A single 10mg/kg/i.p administration of Polyfect (PF; with an intact branching architecture) or Superfect (SF; with a fragmented branching architecture) modulated renal ERK1/2 and p38 MAPK phosphorylation in a dendrimer-specific and animal model-dependent manner. AG1478 treatment (a selective EGFR inhibitor) confirmed that renal ERK1/2 and p38 MAPK signaling was downstream of EGFR. Surprisingly, both PAMAMs induced hyperphosphorylation of ERK1/2 and p38 MAPK (at 1 or 5mg/kg) despite inhibiting EGFR phosphorylation in the diabetic kidney. PAMAMs did not alter renal morphology but their effects on p38 MAPK and EGFR phosphorylation were reversed by ex vivo treatment of kidneys with the anti-oxidant, Tempol. Thus, PAMAMs can intrinsically modulate signaling of mitogen-activated protein kinases (MAPKs) depending on the type of dendrimer (fragmented vs intact branching architecture) and animal model (normal vs diabetic) used and likely occurs via an EGFR-independent and oxidative-stress dependent mechanism. These findings might have important toxicological implications for PAMAM-based delivery systems.