ROCK Inhibition – A New Therapeutic Avenue in Kidney Protection

Abstract

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