Targeted Renal Delivery of Protein Kinase Inhibitors for the Treatment of Chronic Kidney Disease

Fariba      Poosti; Jan-Luuk      Hillebrands; van Goor      van Goor; Martin      H. de Borst

doi:10.2174/157436211795659892

Abstract

The increasing prevalence of end-stage renal disease urges novel therapeutic strategies for the treatment of chronic kidney disease. As protein kinases play a pivotal role in renal inflammation and fibrosis, specific protein kinase inhibitors have been demonstrated to be renoprotective in experimental studies. However, since protein kinases are also involved in key physiological mechanisms such as cell differentiation, cell growth and proliferation, these beneficial effects have been associated with serious side effects, limiting their clinical applicability.

However, the possibility to selectively deliver a drug to cells with a particular phenotype (i.e. cells expressing a cellspecific protein to which drugs can be targeted) has increased the potential of protein kinase inhibitors in chronic kidney disease. Several studies have reported renoprotective effects of protein kinase inhibitors specifically delivered to fibrotic cells, or to specific cell types such as proximal tubular epithelial cells or mesangial cells. An overview of these studies will be provided, as well as future directions in this exciting field of research that may lead to novel highly specific pharmacological intervention strategies.

Keywords: Chronic kidney disease, drug targeting, kidney, pharmacology, protein kinases, renal drug delivery, End-stage renal disease, Rho, ROCK, GTPase, c-Met, Fibrosis, Protein kinsases, EMT, p38 MAP kinase, ERK, Y27632, JNK, c-Jun, Epidermal growth factor receptor, PDGF receptor, Lysozyme, Ras, mitogen, Drug delivery, Mitogen-activated protein kinases, Inflammation, Rho/rac pathway, TGFbeta-receptor