Rho Kinase Inhibition: A New Approach for Treating Diabetic Nephropathy?

Rho family GTPases have received increasing atten-tion as critical regulators of cell function (1).Initially, they were shown to regulate actin dynam-ics, thereby modulating development, cell migra-tion, immune responses, and cancer cell invasion and metastasis. More recent studies have shown that they are also involved in cell-cell adhesion and cell cycle progression. RhoA is one of the most widely studied of the 22 mammalian members of the family, and the serine-threonine kinase Rho kinase (ROCK) is a major RhoA effector. RhoA/ROCK has a number of functions in the kidney. RhoA/ROCK enhances Ca2-dependent vascular smooth muscle contraction, thereby modulating tone (2–4). The potent vasoconstrictor angiotensin II (AngII) activates ROCK in smooth muscle cells. The ROCK inhibitors fa-sudil and Y-27632 dilate afferent and efferent arterioles and reverse AngII-dependent arteriolar vasoconstriction. At the cellular level, RhoA/ROCK mediates cytoskeletal rear-