ROCK Inhibition – A New Therapeutic Avenue in Kidney Protection

摘要: Chronic allograft nephropathy (CAN) remains the main cause of renal transplant loss besides death patients with a functioning graft. Its prevention and treatment still lacks any significant breakthrough since many years (Meier-Kriesche et al. 2004; Pascual 2002). Pathological manifestations CAN include interstitial fibrosis, tubular atrophy, vascular occlusive changes, glomerulosclerosis progressive dysfunction accompanied by hypertension proteinuria (Joosten 2005; Racusen 1999). This histopathologic constellation is now more formally descriptively referred to as fibrosis atrophy (IF/TA) without evidence specific aetiology (Solez 2007). IF/TA or describe common final path different injuries causing damage, whereas their precise pathogenesis complex only incompletely understood 2005). The process encompasses multifactorial aetiologies including alloantigen-dependent well alloantigen-independent factors (Gottmann 2003; Joosten Kerjaschki 2006; Nankivell Reuter 2010; Tullius & Tilney, 1995). Hence, an effective not available so far. Rho effectors Rho-associated, coiled-coil containing protein kinases (ROCK) associated signaling pathways have emerged important players in cardiovascular pathophysiology. Recently, it has been shown that ROCK inhibition protective diabetic obstructive nephropathy, hypertensive nephrosclerosis, ischemia reperfusion injury, chronic (Kanda 2003a; Kentrup D. 10 A.D.; Komers 2011a; 2011b; Liu 2009; Nagatoya 2002; Nishikimi 2004a; Satoh Song 2008; Versteilen 2011). ROCKs initially identified downstream targets small GTP binding Rho. Members family (isoforms A–E, G), Rac 1 2), Cdc42 TC10 (Nobes Hall, 1994). After translocation plasma membrane, GTP-RhoA activates its effectors, two isoforms ROCK, ROCK1 (ROK┚, p160ROCK) ROCK2 (ROK┙, kinase) (Nakagawa 1996). Although, 2 can be differentially regulated under distinct circumstances there no functions at present are serine/threonine belonging AGC (PKA/PKG/PKC) (Ishizaki 1996; Leung 1995; Matsui activity involved actin cytoskeletal organization, stress fiber formation, cell contraction thereby controlling smooth muscle contraction, endothelial barrier leukocyte (e.g., cellular