Novel Therapeutic Targets for the Treatment of Tubulointerstitial Fibrosis

Abstract

Approximately 80% of the kidney is composed of tubular cells which secret and reabsorb substances to and from the urine. Activated tubular cells play a pivotal role in the etiology of renal fibrosis. During renal injury, these activated tubular cells participate in the initiation of fibrogenic processes which eventually may lead to tubulointerstitial fibrosis and end stage renal disease (ESRD). Current therapies such as angiotensin converting enzyme inhibitors, angiotensin II receptor type-1 antagonists and statins do not suffice for the treatment of renal fibrosis. However, in recent years, better understanding of disease mechanisms led to the development of new drug entities that intervene in the signal transduction pathways involved in the disease pathogenesis. This review discusses possible new drugs directed to intracellular signal transduction pathways such as mitogen activated protein kinases (p38, ERK and JNK), growth factors receptor tyrosine kinases (TGF-and PDGF), Rho kinase, and nuclear transcription factors that are activated during disease. In addition to kinase inhibitors, novel approaches such as renal-selective drug targeting, recombinant protein antifibrotic agents and gene silencing concepts are discussed.

Intervention in growth factor activated signaling pathways by renally targeted kinase inhibitors

“…Kinase inhibitors have been approved clinically for cancer only, but preclinical studies demonstrate their potential benefit in the treatment of many other diseases, such as renal fibrosis [6]. In this paper, we have used the kinase inhibitors erlotinib (Tarceva ® ), which is an inhibitor of the EGF receptor kinase and well known for its anti-proliferative actions in cancer [7], and LY364947, an experimental inhibitor of the TGF-β receptor, also known as activin-like kinase (ALK5).…”